ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)
Variation ID: 159748 Accession: VCV000159748.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38116155 (GRCh38) [ NCBI UCSC ] 22: 38512162 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 Mar 16, 2024 Feb 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1799G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Arg600Gln missense NM_001004426.3:c.1637G>A NP_001004426.1:p.Arg546Gln missense NM_001199562.3:c.1637G>A NP_001186491.1:p.Arg546Gln missense NM_001349864.2:c.1799G>A NP_001336793.1:p.Arg600Gln missense NM_001349865.2:c.1637G>A NP_001336794.1:p.Arg546Gln missense NM_001349866.2:c.1637G>A NP_001336795.1:p.Arg546Gln missense NM_001349867.2:c.1265G>A NP_001336796.1:p.Arg422Gln missense NM_001349868.2:c.1121G>A NP_001336797.1:p.Arg374Gln missense NM_001349869.2:c.1103G>A NP_001336798.1:p.Arg368Gln missense NC_000022.11:g.38116155C>T NC_000022.10:g.38512162C>T NG_007094.3:g.103624G>A LRG_1015:g.103624G>A LRG_1015t1:c.1799G>A LRG_1015p1:p.Arg600Gln - Protein change
- R600Q, R374Q, R546Q, R368Q, R422Q
- Other names
- NM_003560.4(PLA2G6):c.1799G>A
- p.Arg600Gln
- Canonical SPDI
- NC_000022.11:38116154:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PLA2G6 | - | - |
GRCh38 GRCh37 |
1039 | 1070 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000147303.6 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV000413569.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 6, 2020 | RCV000578256.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2021 | RCV000624119.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 5, 2023 | RCV001849994.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 24, 2022 | RCV002505129.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2023 | RCV003226213.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002514837.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV003338422.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV003927441.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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iron accumulation in brain
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194676.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Nov 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 2B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited,
maternal
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV000680340.2
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Observation 1:
Sex: female
Tissue: blood
Observation 2:
Sex: female
Tissue: blood
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Likely pathogenic
(Mar 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 2B
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425305.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
Comment:
PLA2G6 c.1799G>A (rs149712244) is rare (<0.1%) in a large population dataset (gnomAD: 11/282490 total alleles; 0.0039%; no homozygotes). Four submitters in ClinVar classify this variant … (more)
PLA2G6 c.1799G>A (rs149712244) is rare (<0.1%) in a large population dataset (gnomAD: 11/282490 total alleles; 0.0039%; no homozygotes). Four submitters in ClinVar classify this variant as either likely pathogenic or pathogenic (Variation ID: 159748). Three bioinformatics tools queried predict that this substitution would be deleterious. Additionally, bioinformatic analysis predicts that this variant would create a cryptic splice acceptor site in exon 13, which may cause abnormal gene splicing. However, this has not been confirmed experimentally to our knowledge. The arginine residue at this position is conserved across all species accessed. This variant in PLA2G6 has been reported previously in the homozygous state in a patient with infantile onset neuroaxonal dystrophy. We consider the c.1799G>A variant to be likely pathogenic. (less)
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Likely pathogenic
(Jun 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448805.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Dec 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741630.4
First in ClinVar: Apr 15, 2018 Last updated: Feb 07, 2023 |
Comment:
The c.1799G>A (p.R600Q) alteration is located in exon 13 (coding exon 12) of the PLA2G6 gene. This alteration results from a G to A substitution … (more)
The c.1799G>A (p.R600Q) alteration is located in exon 13 (coding exon 12) of the PLA2G6 gene. This alteration results from a G to A substitution at nucleotide position 1799, causing the arginine (R) at amino acid position 600 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (11/282490) total alleles studied. The highest observed frequency was 0.02% (6/24928) of African alleles. This alteration has been reported in the homozygous and compound heterozygous states in individuals with PLA2G6-associated neurodegeneration (Davids, 2016; Paisán-Ruiz, 2012; Toth-Bencsik, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922902.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: PLA2G6 c.1799G>A (p.Arg600Gln) results in a conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four … (more)
Variant summary: PLA2G6 c.1799G>A (p.Arg600Gln) results in a conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251096 control chromosomes. c.1799G>A has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation/PLA2G6-associated neurodegeneration (PLAN) disorders (example, PMID: 34272103, 33619735, 26668131, 20619503). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490726.6
First in ClinVar: Jan 09, 2017 Last updated: May 27, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35803092, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35803092, 20619503, 33619735, 34272103, 29472584, 30619057, 20301718, 24745848, 2668131, 34168672, 36790591, 18443314, 26668131) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Infantile osteopetrosis with neuroaxonal dysplasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047719.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.1799G>A(p.Arg600Gln) variant has been reported in individuals affected with Infantile neuroaxonal dystrophy 1 and related disorders(Coro et. al., 2012; Davids et. al., … (more)
The missense variant c.1799G>A(p.Arg600Gln) variant has been reported in individuals affected with Infantile neuroaxonal dystrophy 1 and related disorders(Coro et. al., 2012; Davids et. al., 2016; Paisán-Ruiz, Coro et al., 2012). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Arg600Gln variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.003894% in gnomAD database. The amino acid change p.Arg600Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 600 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101480.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The missense variant p.R600Q in PLA2G6 (NM_003560.4) has been observed previously in individuals affected with Neuroaxonal Dystrophy (Paisán et al, 2012). Experimental studies reveal damaging … (more)
The missense variant p.R600Q in PLA2G6 (NM_003560.4) has been observed previously in individuals affected with Neuroaxonal Dystrophy (Paisán et al, 2012). Experimental studies reveal damaging effect (Davids et al, 2016). The p.R600Q variant is observed in 4/16,216 (0.0247%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties.The p.R600Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 600 of PLA2G6 is conserved in all mammalian species. The nucleotide c.1799 in PLA2G6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The observed variant was also detected in heterozygous state in the proband's mother. (less)
Clinical Features:
Global developmental delay (present) , Abnormality of the mitochondrion (present) , Hypotonia (present) , Respiratory distress (present)
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Likely pathogenic
(Jul 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024664.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002151749.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLA2G6 protein function. ClinVar contains an entry for this variant (Variation ID: 159748). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 20619503, 26668131, 33619735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs149712244, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 600 of the PLA2G6 protein (p.Arg600Gln). (less)
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Likely pathogenic
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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PLA2G6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004744446.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PLA2G6 c.1799G>A variant is predicted to result in the amino acid substitution p.Arg600Gln. This variant has been reported in the compound heterozygous or homozygous … (more)
The PLA2G6 c.1799G>A variant is predicted to result in the amino acid substitution p.Arg600Gln. This variant has been reported in the compound heterozygous or homozygous state in patients with features consistent with PLA2G6-associated neurodegeneration disorder (Paisan-Ruiz et al. 2012. PubMed ID: 20619503; Davids et al. 2016. PubMed ID: 26668131; Bhardwaj et al. 2021. PubMed ID: 34272103). Another missense variant (c.1798C>T, p. Arg600Trp), which affects the same amino acid, has also been reported to be causative for PLA2G6-associated neurodegeneration with infantile and atypical childhood-onset (Illingworth et al. 2014. PubMed ID: 24745848). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(May 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Neurodegeneration with brain iron accumulation 2B Autosomal recessive Parkinson disease 14
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813997.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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PLA2G6-associated neurodegeneration
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003760975.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg600Gln variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 20619503, 34272103, 26668131, 33619735), and has been identified in 0.02% … (more)
The p.Arg600Gln variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 20619503, 34272103, 26668131, 33619735), and has been identified in 0.02% (6/24928) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs149712244). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 159748) and has been interpreted as pathogenic and likely pathogenic by multiple submitters. Of the 4 affected individuals, 1 was a compound heterozygote that carried reported likely pathogenic variants in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg600Gln variant is pathogenic (VariantID: 265448; PMID: 20619503, 34272103, 26668131). In vitro functional studies provide some evidence that the p.Arg600Gln variant may impact protein function (PMID: 26668131). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 1197568). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PP3, PM5_supporting, PM3_strong, PS3_supporting (Richards 2015). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India. | Bhardwaj NK | Brain & development | 2021 | PMID: 34272103 |
New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family. | Toth-Bencsik R | Frontiers in genetics | 2021 | PMID: 34168672 |
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. | Brunet T | Clinical genetics | 2021 | PMID: 33619735 |
PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. | Guo YP | Frontiers in neurology | 2018 | PMID: 30619057 |
The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization. | Malley KR | Nature communications | 2018 | PMID: 29472584 |
PLA2G6-Associated Neurodegeneration. | Adam MP | - | 2017 | PMID: 20301718 |
Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. | Davids M | Journal of medical genetics | 2016 | PMID: 26668131 |
PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. | Illingworth MA | Molecular genetics and metabolism | 2014 | PMID: 24745848 |
Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. | Paisán-Ruiz C | Neurobiology of aging | 2012 | PMID: 20619503 |
Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). | Kurian MA | Neurology | 2008 | PMID: 18443314 |
[Keratoplasty in unsuspected corneal cancer--case report]. | Daxecker F | Fortschritte der Ophthalmologie : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft | 1989 | PMID: 2668131 |
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Text-mined citations for rs149712244 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.