ClinVar Miner

Submissions for variant NM_176787.5(PIGN):c.1694G>T (p.Arg565Leu) (rs201835155)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418646 SCV000534047 likely pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The R565L variant in the PIGN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It was observed with a pathogenic variant on the opposite allele (in trans) in a patient referred for genetic testing at GeneDx. The R565L 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 R565L variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.1694 G>T (aka R565L) destroys the splice acceptor site in intron 18, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. We interpret R565L as a likely pathogenic variant.
Invitae RCV000695519 SCV000824025 uncertain significance Multiple congenital anomalies-hypotonia-seizures syndrome 1 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 565 of the PIGN protein (p.Arg565Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs201835155, ExAC no frequency). This variant has not been reported in the literature in individuals with PIGN-related disease. ClinVar contains an entry for this variant (Variation ID: 391067). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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