Submissions for variant NM_000271.5(NPC1):c.3100G>C (p.Gly1034Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002617205	SCV002956918	likely pathogenic	Niemann-Pick disease, type C1	2022-11-06	criteria provided, single submitter	clinical testing	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. This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 31743419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1034 of the NPC1 protein (p.Gly1034Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526937	SCV005039912	likely pathogenic	Niemann-Pick disease, type C	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3100G>C (p.Gly1034Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251442 control chromosomes. c.3100G>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Guan_2020). Additionally, another missense variant resulting in the same amino acid change (c.3100G>A, p.Gly1034Arg) has been observed in several individuals with Niemann Pick Disease (PMID: 15774455, 35086560). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31743419). ClinVar contains an entry for this variant (Variation ID: 1918189). Based on the evidence outlined above, the variant was classified as likely pathogenic.