ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2201G>T (p.Ser734Ile) (rs757475924)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414597 SCV000491262 likely pathogenic not provided 2015-12-17 criteria provided, single submitter clinical testing The S734I variant in the NPC1 gene has been reported previously in association with Niemann-Pick Disease Type C, in affected individuals when present in the homozygous state or when heterozygous with another variant (Park et al., 2003; Macias-Vidal et al., 2014; Imrie et al., 2015). Functional studies showed no difference in protein expression when compared to wild type, suggesting the S734I variant has no effect on folding or degradation but could directly affect protein functionality (Macias-Vidal et al., 2014). The S734I variant was not observed in approximately 6,500 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 S734I 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 Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G729E, P733R) have been reported in the Human Gene Mutation Database in association with Niemann-Pick Disease Type C (Stenson et al., 2014), supporting the functional importance of this region of the protein. The S734I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000667438 SCV000791882 likely pathogenic Niemann-Pick disease type C1 2017-05-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414597 SCV000858711 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing
Invitae RCV000667438 SCV001417098 pathogenic Niemann-Pick disease type C1 2019-04-12 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 734 of the NPC1 protein (p.Ser734Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs757475924, ExAC 0.009%). This variant has been observed in several individuals affected with NPC1-related conditions (PMID: 12955717, 26666848, 20718790, 23433426). ClinVar contains an entry for this variant (Variation ID: 372775). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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