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rs121908686

  • Pathogenic/Likely pathogenic

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Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the PLA2G6 protein (p.Arg741Gln). This variant is present in population databases (rs121908686, gnomAD 0.05%). This missense change has been observed in individuals with dystonia-parkinsonism (PMID: 18570303, 20669327, 26196026, 26668131, 27268037). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6203). 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. For these reasons, this variant has been classified as Pathogenic.

Functional analyses have not demonstrated a consistent damaging effect of this variant on protein activity (Engel et al., 2010; Chiu et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32707456, 24182522, 31196701, 26196026, 20669327, 26668131, 18570303, 27268037, 25601130, 29108286, 20886109)

A homozygous missense variation in exon 16 of the PLA2G6 gene that results in the amino acid substitution of Glutamine for Arginine at codon 741 was detected. The observed variation has not been reported in 1000 genomes and has a minor allele frequency of 0.02% in ExAc database. The in silico predictions of the variant are probably damaging by Polyphen-2 (HumDiv) and damaging by Mutation Taster2. The reference codon is conserved across mammals. The observed variant has previously been observed in patients with adult onset dystonia Parkinsonism (Pasian-Ruiz et al. 2009). In summary, the variant meets our criteria to be classified as likely pathogenic.

Reference Allele

C


Alternative Allele

T

Chromosome

22


Location

38112558


Variant Type

SNP

Genes

ClinVar

Name

NM_003560.4(PLA2G6):c.2222G>A (p.Arg741Gln)


Allele

T


Clinical Significance

Pathogenic/Likely pathogenic

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