ClinVar Genomic variation as it relates to human health

The p.Asp739His variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 30120687, 18799783), segregated with disease in 1 affected relative from 1 family (PMID: 18799783), and has been identified in 0.006% (1/17170) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs587784349). 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#: 159761) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services and Invitae, and pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Asp739His variant is pathogenic (PMID: 30120687). 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, the clinical significance of the p.Asp739His variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3_supporting (Richards 2015).

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 739 of the PLA2G6 protein (p.Asp739His). This variant is present in population databases (rs587784349, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 16783378; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159761). 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%. For these reasons, this variant has been classified as Pathogenic.

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: 16783378, 30120687, 18799783)

The PLA2G6 c.2215G>C (p.Asp739His) variant has been reported in a compound heterozygous state with another missense variant in two related patients with atypical neuroaxonal dystrophy, which was initially categorized as idiopathic neurodegeneration with brain iron accumulation (Morgan et al. 2006; Gregory et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the Total population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Asp739His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.2215G>C (p.D739H) alteration is located in exon 16 (coding exon 15) of the PLA2G6 gene. This alteration results from a G to C substitution at nucleotide position 2215, causing the aspartic acid (D) at amino acid position 739 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.