ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.2128C>T (p.Arg710Cys)

gnomAD frequency: 0.00001  dbSNP: rs587784347
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147314 SCV000194687 likely pathogenic Iron accumulation in brain 2013-02-08 criteria provided, single submitter clinical testing
Mendelics RCV000537119 SCV002518871 pathogenic Infantile neuroaxonal dystrophy 2022-05-04 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002515979 SCV003761471 uncertain significance PLA2G6-associated neurodegeneration 2023-01-24 criteria provided, single submitter curation The p.Arg710Cys variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 31493945), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784347). 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#: 159759) and has been interpreted as pathogenic by Genetic Services Laboratory (University of Chicago) and Undiagnosed Diseases Network (NIH). Of the 2 affected individuals, one of those was a homozygote, which increases the likelihood that the p.Arg710Cys variant is pathogenic (PMID: 31493945; ClinVar ID#: 159759). 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, the clinical significance of the p.Arg710Cys variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP3, PM2_supporting (Richards 2015).
Undiagnosed Diseases Network, NIH RCV000537119 SCV000622145 likely pathogenic Infantile neuroaxonal dystrophy 2016-04-13 no assertion criteria provided clinical testing Variant previously reported in two other patients with this phenotype tested the by the same laboratory (one listed in ClinVar). One patient was reportedly homozygous for this variant, while the other was compound heterozygous. Variant is rare (2 heterozygotes in ExAC). Likely pathogenicity given patient’s phenotype consistent with known phenotype associated with gene, infantile neuroaxonal dystrophy (MIM 256600), homozygous rare variant in patient with consanguineous parents, variant reportedly identified in two other patients with this phenotype.

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