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rs587784349

  • Conflicting interpretations of pathogenicity

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Description

The D739H variant in the PLA2G6 gene has been reported previously in patients with atypical NAD who were also heterozygous for a second variant in the gene (Morgan et al., 2006; Gregory et al., 2008). The D739H 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 D739H variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G740R, R741W, R741Q) have been reported in the Human Gene Mutation Database in association with PLA2G6-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret D739H as a pathogenic variant.

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.

Reference Allele

C


Alternative Allele

G

Chromosome

22


Location

38112565


Variant Type

SNP

Genes

ClinVar

Name

NM_003560.4(PLA2G6):c.2215G>C (p.Asp739His)


Allele

G


Clinical Significance

Conflicting interpretations of pathogenicity

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