Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Myriad Genetics, |
RCV000003102 | SCV002060046 | uncertain significance | Niemann-Pick disease, type C1 | 2021-11-16 | criteria provided, single submitter | clinical testing | NM_000271.4(NPC1):c.2873G>A(R958Q) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease type C1. R958Q has been observed in cases with relevant disease (PMID: 11349231, 17160617, 23433426). Functional assessments of this variant are available in the literature (PMID: 28193631, 31699992). R958Q has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, there is insufficient evidence to classify NM_000271.4(NPC1):c.2873G>A(R958Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. |
Invitae | RCV000003102 | SCV002252336 | likely pathogenic | Niemann-Pick disease, type C1 | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 958 of the NPC1 protein (p.Arg958Gln). This variant is present in population databases (rs120074132, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11349231). ClinVar contains an entry for this variant (Variation ID: 2968). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg958 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 11754101, 35086560), which suggests that this may be a clinically significant amino acid residue. 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. |
Foundation for Research in Genetics and Endocrinology, |
RCV000003102 | SCV002578226 | pathogenic | Niemann-Pick disease, type C1 | 2022-08-08 | criteria provided, single submitter | clinical testing | A compound heterozygous missense variation in exon 19 of the NPC1 gene that results in the amino acid substitution of Glutamine for Arginine at codon 958 was detected. The observed variant c.2873G>A (p.Arg958Gln) has not been reported in the 1000 genomes and has a MAF of 0.0002% and 0.001% in the gnomAD databases . The in silico prediction of the variant are possibly damaging by Mutation Taster, DANN, LRT, and SIFT. The reference codon is conserved across species. |
OMIM | RCV000003102 | SCV000023260 | pathogenic | Niemann-Pick disease, type C1 | 2001-06-01 | no assertion criteria provided | literature only |