ClinVar Genomic variation as it relates to human health

The p.Ala499Thr variant in PLA2G6 has been reported in 1 individual, in the homozygous state, with PLA2G6-associated neurodegeneration (PMID: 27942883), segregated with disease in 1 affected relative in 1 family, and has been identified in 0.006% (1/17748) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs141045127). 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#: 803693) and has been interpreted as likely pathogenic by Mendelics and as a variant of uncertain significance by Invitae. 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.Ala499Thr variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3_supporting (Richards 2015).

The PLA2G6 c.1495G>A variant is predicted to result in the amino acid substitution p.Ala499Thr. This variant has been reported with a second PLA2G6 variant or in the homozygous state in individuals with early-onset dystonia-parkinsonism, early onset (Yamashita et al. 2017. PubMed ID: 27942883; Miki et al. 2017. PubMed ID: 28211602; Chen et al. 2022. PubMed ID: 36033628). An alternative nucleotide change affecting the same amino acid (p.Ala499Val) has been reported in an individual with infantile neuroaxonal dystrophy (Zhang et al. 2013. PubMed ID: 22934738). This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-38519198-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 499 of the PLA2G6 protein (p.Ala499Thr). 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 PLA2G6-related conditions (PMID: 27942883; Invitae). ClinVar contains an entry for this variant (Variation ID: 803693). 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%. This variant disrupts the p.Ala499 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 22934738), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: PLA2G6 c.1495G>A (p.Ala499Thr) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-06 in 160002 control chromosomes. c.1495G>A has been reported in the literature in two siblings affected with Parkinsons disease (example, Yamashita_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32771225, 28211602, 27942883). ClinVar contains an entry for this variant (Variation ID: 803693). Based on the evidence outlined above, the variant was classified as likely pathogenic.