Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001892286 | SCV002154939 | pathogenic | Niemann-Pick disease, type C1 | 2021-08-14 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with leucine at codon 667 of the NPC1 protein (p.Ser667Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change alters NPC1 gene expression (PMID: 16143556). 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: 16143556). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). |
| Foundation for Research in Genetics and Endocrinology, |
RCV001892286 | SCV005199941 | pathogenic | Niemann-Pick disease, type C1 | 2024-08-24 | criteria provided, single submitter | clinical testing | A heterozygous variant c.2000C>T in exon 13 of the NPC1 gene that results in the amino acid substitution of Leucine for Serine at codon 667 was detected. The observed variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions is damaging by MutationTaster, DANN and FATHMM. In summary, the variant meets our criteria to be classified as pathogenic. |