ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.991G>A (p.Asp331Asn)

dbSNP: rs199935023
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626136 SCV000746766 uncertain significance Infantile neuroaxonal dystrophy 2023-12-30 criteria provided, single submitter clinical testing
Invitae RCV000626136 SCV000826955 uncertain significance Infantile neuroaxonal dystrophy 2021-08-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 331 of the PLA2G6 protein (p.Asp331Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs199935023, ExAC 0.01%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 21368765). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000762072 SCV000892327 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001146572 SCV001307322 uncertain significance PLA2G6-associated neurodegeneration 2017-09-05 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV000762072 SCV002525266 uncertain significance not provided 2022-05-27 criteria provided, single submitter clinical testing Identified in the single heterozygous state, without a second PLA2G6 variant identified, in patients with Parkinson's disease (Tomiyama et al., 2011; Daida et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22213678, 21368765, 23182313, 32771225)
Broad Institute Rare Disease Group, Broad Institute RCV001146572 SCV003761013 uncertain significance PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Asp331Asn variant in PLA2G6 has not been previously reported in the literature in individuals with PLA2G6-associated neurodegeneration but has been identified in 0.009% (7/81550) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199935023). 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#: 522939) and has been interpreted as pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences) and as a variant of uncertain significance by Invitae, CeGaT Center for Human Genetics Tuebingen, and Illumina Laboratory Services (Illumina). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp331Tyr, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 29454663, 31196701, 22213678/Variation ID: 30371). In summary, the clinical significance of the p.Asp331Asn variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting, PM5 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155254 SCV003844630 uncertain significance not specified 2023-12-15 criteria provided, single submitter clinical testing Variant summary: PLA2G6 c.991G>A (p.Asp331Asn) results in a conservative amino acid change located in the Ankyrin repeat (IPR002110) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 164594 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.991G>A has been reported in the literature in at least one individual affected with Parkinson's disease (Tomiyama_2011, Daida_2021). These report(s) do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32771225, 21368765). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (n=5) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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