ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1442T>A (p.Leu481Gln)
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.1442T>A (p.Leu481Gln)
Variation ID: 159731 Accession: VCV000159731.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38519251 (GRCh37) [ NCBI UCSC ] 22: 38123244 (GRCh38) [ 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 Feb 14, 2024 Jan 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1442T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Leu481Gln missense NM_001004426.3:c.1280T>A NP_001004426.1:p.Leu427Gln missense NM_001199562.3:c.1280T>A NP_001186491.1:p.Leu427Gln missense NM_001349864.2:c.1442T>A NP_001336793.1:p.Leu481Gln missense NM_001349865.2:c.1280T>A NP_001336794.1:p.Leu427Gln missense NM_001349866.2:c.1280T>A NP_001336795.1:p.Leu427Gln missense NM_001349867.2:c.908T>A NP_001336796.1:p.Leu303Gln missense NM_001349868.2:c.764T>A NP_001336797.1:p.Leu255Gln missense NM_001349869.2:c.746T>A NP_001336798.1:p.Leu249Gln missense NC_000022.11:g.38123244A>T NC_000022.10:g.38519251A>T NG_007094.3:g.96535T>A LRG_1015:g.96535T>A LRG_1015t1:c.1442T>A LRG_1015p1:p.Leu481Gln - Protein change
- L481Q, L249Q, L427Q, L303Q, L255Q
- Other names
- NM_003560.4(PLA2G6):c.1442T>A
- p.Leu481Gln
- Canonical SPDI
- NC_000022.11:38123243:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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 |
- | 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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May 21, 2013 | RCV000147286.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2020 | RCV000995605.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 18, 2022 | RCV002051814.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002514831.2 |
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
(May 21, 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: SCV000194659.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318587.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000159731, PMID:16783378). In silico … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000159731, PMID:16783378). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.962>=0.6, 3CNET: 0.995>=0.75). A missense variant is a common mechanism. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000059). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16783378). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Muscular atrophy (present) , Seizure (present) , Inability to walk (present)
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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: SCV003760997.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Leu481Gln variant in PLA2G6 has been reported in 8 individuals with PLA2G6-associated neurodegeneration (PMID: 18359254, Silva 2014, Pinto 2010, 16783378, Lissens 2008, 24870368, 25164370), … (more)
The p.Leu481Gln variant in PLA2G6 has been reported in 8 individuals with PLA2G6-associated neurodegeneration (PMID: 18359254, Silva 2014, Pinto 2010, 16783378, Lissens 2008, 24870368, 25164370), and has been identified in 0.004% (1/25880) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784330). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 159731) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago) and Institute of Human Genetics (Klinikum rechts der Isar). Of the 8 affected individuals, 2 of those were homozygotes, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.Leu481Gln variant is pathogenic. (Variant ID: 6195; PMID: 18359254, 25164370). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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, PM2_supporting, PM3_strong (Richards 2015). (less)
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Pathogenic
(May 18, 2022)
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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: SCV003262979.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 481 of the PLA2G6 protein (p.Leu481Gln). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 481 of the PLA2G6 protein (p.Leu481Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with PLA2G6-related conditions (PMID: 16783378, 24870368, 25164370). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 159731). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 16, 2020)
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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
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV001149881.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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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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Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. | Romani M | European journal of neurology | 2015 | PMID: 25164370 |
A case of infantile neuroaxonal dystrophy of neonatal onset. | Fusco C | Journal of child neurology | 2015 | PMID: 24870368 |
PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. | Morgan NV | Nature genetics | 2006 | PMID: 16783378 |
Text-mined citations for rs587784330 ...
HelpRecord last updated Mar 30, 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.