ClinVar Genomic variation as it relates to human health

Variant summary: PLA2G6 c.1894C>T (p.Arg632Trp) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-06 in 223138 control chromosomes. c.1894C>T has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (example Sina_2009, Morgan_2006) and subsequently cited by others (example, Kapoor_2016, pei Guo_2018, Giri_2016, Shen_2019, Tsai Chu_2020, and Yup Lee_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a damaging effect, where phospholipase catalytic activity increased, supporting a gain of function effect (Engel et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19087156, 30619057, 16783378, 20886109)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 632 of the PLA2G6 protein (p.Arg632Trp). 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 individuals with PLA2G6 associated conditions (PMID: 16783378, 19087156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6199). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PLA2G6 function (PMID: 20886109, 29108286, 34520727). For these reasons, this variant has been classified as Pathogenic.

The p.Arg632Trp variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 19087156), segregated with disease in 2 affected relatives from 1 family (PMID: 19087156), and has been identified in 0.009% (2/21698) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908683). 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#: 6199) and has been interpreted as pathogenic by OMIM, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and CeGaT Praxis fuer Humangenetik Tuebingen. Of the 2 affected individuals, 1 of those was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg632Trp variant is pathogenic (Variant ID: 6198; PMID: 16783378, 19087156). The functional evidence for this variant is conflicting, and may not accurately depict the pathogenicity of the variant (PMID: 20886109, 29108286). 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: PM3, PP1_moderate, PP3, PM2_supporting (Richards 2015).