Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV003501740 | SCV004297804 | pathogenic | Niemann-Pick disease, type C1 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 724 of the NPC1 protein (p.Leu724Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 11333381). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. Studies have shown that this missense change alters NPC1 gene expression (PMID: 11333381). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV005240831 | SCV005887275 | likely pathogenic | Niemann-Pick disease, type C | 2025-01-14 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.2171T>C (p.Leu724Pro) results in a non-conservative amino acid change located in the Sterol-sensing domain (SSD) (IPR000731) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250816 control chromosomes. c.2171T>C has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease Type C (e.g. Millat_2001, Sevin_2007, Freihuber_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing near null NPC1 protein levels in compound heterozygous patient fibroblasts, slightly elevated baseline cholesterol accumulation in lysosomal storage organelles in vitro, and significantly altered trafficking compared to WT in vitro (e.g. Millat_2001, Sevin_2007, Freihuber_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37480097, 11333381, 28193631, 17003072, 31509197). ClinVar contains an entry for this variant (Variation ID: 2736708). Based on the evidence outlined above, the variant was classified as likely pathogenic. |