ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His) (rs535486098)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147294 SCV000194667 likely pathogenic Iron accumulation in brain 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000412963 SCV000490725 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing The R538H variant in the PLA2G6 gene has been reported previously in the homozygous state in individuals with infantile neuroaxonal dystrophy (INAD) (Megahed et al., 2016; Kapoor et al., 2016). The R538H variant has also been observed with a pathogenic variant on the opposite allele (in trans) in multiple patients referred for genetic testing at GeneDx with features suggestive of PLA2G6-related disorders. The R538H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R538H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A different missense variant in the same codon (R538C) has been reported in association with INAD (Morgan et al., 2006; Gregory et al., 2008; Riku et al.,2013), supporting the functional importance of this residue. We interpret R538H as a pathogenic variant.

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