Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV003606698 | SCV004514421 | likely pathogenic | Niemann-Pick disease, type C1 | 2022-11-29 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Ser734 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12955717, 20718790, 23433426, 26666848). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 variant has not been reported in the literature in individuals affected with NPC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 734 of the NPC1 protein (p.Ser734Thr). 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, |
RCV004527004 | SCV005040224 | uncertain significance | not specified | 2024-03-15 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.2201G>C (p.Ser734Thr) results in a conservative amino acid change located in the Sterol-sensing domain (IPR000731) of 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 251276 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2201G>C in individuals affected with Niemann-Pick Disease Type C and no experimental evidence demonstrating its impact on protein function have been reported. Another missense variant in the same residue (p.Ser734Ile) has been classified as pathogenic in our lab, however additional evidence is needed to make unequivocal conclusions about this variant. ClinVar contains an entry for this variant (Variation ID: 2888215). Based on the evidence outlined above, the variant was classified as uncertain significance. |