ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1077G>A (p.Ser359=)
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.1077G>A (p.Ser359=)
Variation ID: 279875 Accession: VCV000279875.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38132831 (GRCh38) [ NCBI UCSC ] 22: 38528838 (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 Dec 6, 2016 Mar 5, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1077G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Ser359= synonymous NM_001004426.3:c.1077G>A NP_001004426.1:p.Ser359= synonymous NM_001199562.3:c.1077G>A NP_001186491.1:p.Ser359= synonymous NM_001349864.2:c.1077G>A NP_001336793.1:p.Ser359= synonymous NM_001349865.2:c.1077G>A NP_001336794.1:p.Ser359= synonymous NM_001349866.2:c.1077G>A NP_001336795.1:p.Ser359= synonymous NM_001349867.2:c.543G>A NP_001336796.1:p.Ser181= synonymous NM_001349868.2:c.399G>A NP_001336797.1:p.Ser133= synonymous NM_001349869.2:c.543G>A NP_001336798.1:p.Ser181= synonymous NC_000022.11:g.38132831C>T NC_000022.10:g.38528838C>T NG_007094.3:g.86948G>A LRG_1015:g.86948G>A LRG_1015t1:c.1077G>A LRG_1015p1:p.Ser359= - Protein change
- Other names
- NM_003560.4(PLA2G6):c.1077G>A
- p.Ser359=
- Canonical SPDI
- NC_000022.11:38132830: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
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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Oct 18, 2022 | RCV000266508.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV001382039.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002519034.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 3, 2021 | RCV002479994.2 |
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
(Aug 03, 2021)
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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: SCV002789018.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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: SCV003761007.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Ser359= variant in PLA2G6 has been reported in at least 8 individuals with PLA2G6-associated neurodegeneration (PMID: 22934738, 29159939, Lu_2017, 32005694, 27395053, 22213678), and has … (more)
The p.Ser359= variant in PLA2G6 has been reported in at least 8 individuals with PLA2G6-associated neurodegeneration (PMID: 22934738, 29159939, Lu_2017, 32005694, 27395053, 22213678), and has been identified in 0.02% (2/12982) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs368497893). 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#: 279875) and has been interpreted as pathogenic by GeneDx and Invitae. Of the 8 affected individuals, 2 of those were homozygotes, and 3 were compound heterozygotes that carried reported likely pathogenic variants with unknown phase, which increases the likelihood that the p.Ser359= variant is pathogenic. (Variant ID: 437465, 129889; PMID: 22934738, 29159939, Lu_2017, 32005694). In vitro functional studies provide some evidence that the p.Ser359= variant may slightly impact protein function (PMID: 22213678). 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3_very-strong, PS3_moderate, PP3 (Richards 2015). (less)
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Pathogenic
(Oct 18, 2022)
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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: SCV000329471.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate the use of a cryptic donor site, resulting in a frameshift variant resulting in a null allele, and this is a … (more)
Published functional studies demonstrate the use of a cryptic donor site, resulting in a frameshift variant resulting in a null allele, and this is a gene for which loss of function is a known mechanism of disease (Lu et al., 2012); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 22213678, 26633542, 31589614, 29159939, 32005694, 27395053, 22934738, 32183746) (less)
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Pathogenic
(Jan 22, 2024)
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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: SCV001580644.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 359 of the PLA2G6 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 359 of the PLA2G6 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PLA2G6 protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. 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 variant has been observed in individuals with PLA2G6-related conditions (PMID: 22213678, 22934738, 26196026, 27395053, 29159939). ClinVar contains an entry for this variant (Variation ID: 279875). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive Parkinson disease 14
Neurodegeneration with brain iron accumulation 2B Infantile neuroaxonal dystrophy
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
inherited
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Molecular Genetics Lab, CHRU Brest
Accession: SCV004697616.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
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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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Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities. | Xiao B | American journal of medical genetics. Part A | 2018 | PMID: 29159939 |
Identification of Novel Compound Mutations in PLA2G6-Associated Neurodegeneration Patient with Characteristic MRI Imaging. | Guo S | Molecular neurobiology | 2017 | PMID: 27395053 |
PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review. | Karkheiran S | Tremor and other hyperkinetic movements (New York, N.Y.) | 2015 | PMID: 26196026 |
Follow-up study of 25 Chinese children with PLA2G6-associated neurodegeneration. | Zhang P | European journal of neurology | 2013 | PMID: 22934738 |
PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease. | Lu CS | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2012 | PMID: 22213678 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs368497893 ...
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.