ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.481C>T (p.Arg161Cys)

gnomAD frequency: 0.00004  dbSNP: rs767260174
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001583780 SCV001820129 uncertain significance not provided 2020-01-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001866173 SCV002140643 uncertain significance Infantile neuroaxonal dystrophy 2024-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the PLA2G6 protein (p.Arg161Cys). This variant is present in population databases (rs767260174, gnomAD 0.01%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 35861376). ClinVar contains an entry for this variant (Variation ID: 1214690). 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 with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002495942 SCV002781693 uncertain significance Infantile neuroaxonal dystrophy; Neurodegeneration with brain iron accumulation 2B; Autosomal recessive Parkinson disease 14 2021-10-29 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV005412269 SCV006079742 uncertain significance PLA2G6-associated neurodegeneration 2025-04-30 criteria provided, single submitter curation The p.Arg161Cys variant in PLA2G6 has been reported in one individual with PLA2G6-associated neurodegeneration (PMID: 35861376), and has been identified in 0.005% (3/60004) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784351). 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 (VCV001214690.10) and has been interpreted as a variant of uncertain significance by Fulgent Genetics, GeneDx, and Labcorp Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg161Cys variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015).

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