ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2140C>T (p.Arg714Cys)

gnomAD frequency: 0.00001  dbSNP: rs770762664
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001905708 SCV002156048 uncertain significance Niemann-Pick disease, type C1 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 714 of the NPC1 protein (p.Arg714Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1386174). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV002261404 SCV002541455 uncertain significance not provided 2022-01-03 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004749766 SCV005361198 uncertain significance NPC1-related disorder 2024-04-24 no assertion criteria provided clinical testing The NPC1 c.2140C>T variant is predicted to result in the amino acid substitution p.Arg714Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0045% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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