ClinVar Miner

Submissions for variant NM_003560.4(PLA2G6):c.991G>T (p.Asp331Tyr) (rs199935023)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498427 SCV000589613 pathogenic not provided 2017-06-02 criteria provided, single submitter clinical testing The D331Y variant in the PLA2G6 gene has been reported previously either in the homozygous state or in trans with another pathogenic PLA2G6 variant in several individuals with early-onset parkinsonism (Shi et al., 2011; Lu et al., 2012; Xie et al., 2015). The D331Y variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D331Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In vitro functional studies demonstrate that D331Y is associated with a 70% reduction in enzyme activity (Shi et al., 2011). Missense variants in a nearby residue (R329C, R329H) have been reported in the Human Gene Mutation Database in association with infantile neuroaxonal dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret D331Y as a pathogenic variant.
OMIM RCV000023319 SCV000044610 pathogenic Parkinson disease 14 2011-07-05 no assertion criteria provided literature only

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