Variants
Sign InSign Up

rs530348521

  • Pathogenic

Your Genotype

Sign In

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the PLA2G6 protein (p.Arg741Trp). 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 clinical features of infantile neuroaxonal dystrophy (PMID: 16783378, 25164370, 31516627). ClinVar contains an entry for this variant (Variation ID: 265448). 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. Experimental studies have shown that this missense change affects PLA2G6 function (PMID: 20886109). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg741 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18570303, 20669327, 26196026, 26668131, 27268037). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant has been previously reported as a compound heterozygous or homozygous change inindividuals with Infantile Neuroaxonal Dystrophy (PMID: 20886109, 25164370, 16783378). In vitro enzyme assays demonstrated that the p.Arg741Trp amino acid substitution reduced PLA2G6 enzyme activity (PMID: 20886109). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (1/148108), and thus is presumed to be rare. The c.2221C>T (p.Arg741Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2221C>T (p.Arg741Trp) variant is classified as Pathogenic.

The R741W variant in the PLA2G6 gene has been reported previously in association with INAD when present in the homozygous state or when present with another missense variant in PLA2G6 (Morgan et al, 2006; Romani et al 2015). The R741W variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R741W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In vitro enzyme assays demonstrated that the R741W amino acid substitution reduced PLA2G6 enzyme activity (Engel et al., 2010). We interpret R741W as a pathogenic variant.

Reference Allele

G


Alternative Allele

A

C

Chromosome

22


Location

38112559


Variant Type

SNP

Genes

ClinVar

Name

NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)


Allele

A


Clinical Significance

Pathogenic

© 2024 Biocodify. All rights reserved.

TwitterTwitter

Product

HomePricingDashboard

Stay up to date

The latest news and updates from Biocodify, sent to your inbox.