ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2780C>T (p.Ala927Val)

gnomAD frequency: 0.00002  dbSNP: rs753768576
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668027 SCV000792570 likely pathogenic Niemann-Pick disease, type C1 2017-07-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000668027 SCV002234171 pathogenic Niemann-Pick disease, type C1 2024-10-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 927 of the NPC1 protein (p.Ala927Val). This variant is present in population databases (rs753768576, gnomAD 0.01%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 11545687, 27366019, 27549128). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552715). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000668027 SCV003824121 pathogenic Niemann-Pick disease, type C1 2022-06-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689840 SCV005185669 pathogenic Niemann-Pick disease, type C 2024-05-16 criteria provided, single submitter clinical testing Variant summary: NPC1 c.2780C>T (p.Ala927Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251354 control chromosomes. c.2780C>T has been reported in the literature as homozygous or in compound heterozygous state with a pathogenic variant in multiple individuals affected with Niemann-Pick Disease Type C (Meiner_2001, Lee_2016, Cervera-Gaviria_2016, Hwang_2023). This variant has also been shown to segregate with disease in at least two families (Meiner_2001, Lee_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27549128, 32222928, 36636588, 27366019, 11545687). ClinVar contains an entry for this variant (Variation ID: 552715). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV004721537 SCV005327314 likely pathogenic not provided 2024-03-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9400363, 34535129, 11545687, 27549128, 27366019, 32222928, 33767182)

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