ClinVar Genomic variation as it relates to human health

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.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006203). A different missense change at the same codon (p.Arg741Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265448). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: PLA2G6 c.2222G>A (p.Arg741Gln) results in a conservative amino acid change in the encoded protein sequence. Three 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-05 in 154980 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 causing Neurodegeneration With Brain Iron Accumulation (9e-05 vs 0.00085), allowing no conclusion about variant significance. c.2222G>A has been reported in the literature in multiple individuals affected with dystonia-parkinsonism, with homozygous individuals reported and family members showing segregation of the variant with potential low penetrance (Paisan-Ruiz_2009, Bohlega_2016, Kumar_2020). These data indicate that the variant is very likely to be associated with disease. A different variant at the same amino acid has been reported as pathogenic by ClinVar (p.Arg741Trp). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The observed missense c.2222G>A (p.Arg741Gln) variant in PLA2G6 gene has been previously reported in homozygous state in multiple individuals affected with PLA2G6-related disorders (Paisán-Ruiz et al., 2010; Bohlega et al., 2016; Kumar et al., 2020). This variant has been observed to segregate with disease (Paisán-Ruiz et al., 2010). Functional studies showed that this variant is unable to maintain mitochondrial function and is defective in preventing mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway (Chiu et al., 2017). The p.Arg741Gln variant has been reported with allele frequency of 0.009% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid change p.Arg741Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 741 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. 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 (PMID: 20886109, 29108286); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18570303, 27268037, 29108286, 25601130, 31196701, 26668131, 20669327, 26196026, 24182522, 35499206, 35113461, 35016069, 31069529, 35329915, 35803092, 35152491, 34622992, 32183746, 35911906, 34520727, 32707456, 32860008, 35005075, 34758253, 20886109, 34272103, 33452780, 34365112)

PP1_strong, PM2_moderate, PM3_strong, PM5

Variant confirmed as disease-causing by referring clinical team