Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001265934 | SCV001444106 | likely pathogenic | Inborn genetic diseases | 2019-02-11 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001880105 | SCV002241900 | pathogenic | Niemann-Pick disease, type C1 | 2023-08-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala926 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22326530, 23433426, 27250337, 32860008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 985168). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 16098014, 32138288, 32222928). This variant is present in population databases (rs564631426, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 926 of the NPC1 protein (p.Ala926Thr). |
Foundation for Research in Genetics and Endocrinology, |
RCV001880105 | SCV002583243 | pathogenic | Niemann-Pick disease, type C1 | 2022-08-08 | criteria provided, single submitter | clinical testing | A compound heterozygous missense variation in exon 18 of the NPC1 gene that results in the amino acid substitution of Threonine for Alanine at codon 926 was detected. The observed variant c.2776G>A (p.Ala926Thr) 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.Therefore, the variant meets our criteria to be classified as pathogenic based on absence from controls and in silico prediction models. |