ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2728G>A (p.Gly910Ser) (rs768999208)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000258915 SCV000328675 likely pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing The G910S variant in the NPC1 gene has been reported previously in a male with clinical and biochemical features of classic Niemann-Pick disease type C who also harbored another missense variant in the NPC1 gene (Tarugi et al., 2002). The G910S variant was not observed in approximately 6500 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 G910S 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 that is conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, we interpret G910S as a likely pathogenic variant.
Counsyl RCV000674176 SCV000799465 likely pathogenic Niemann-Pick disease type C1 2018-04-18 criteria provided, single submitter clinical testing
Invitae RCV000674176 SCV000934824 pathogenic Niemann-Pick disease type C1 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 910 of the NPC1 protein (p.Gly910Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs768999208, ExAC 0.001%). This variant has been observed in several individuals with Niemann-Pick type C (PMID: 12401890, 26108224, 27706244, 28480683, 28802248, 29197565). ClinVar contains an entry for this variant (Variation ID: 268187). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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