Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002605692 | SCV002977386 | pathogenic | Niemann-Pick disease, type C1 | 2022-05-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. A different variant (c.2524T>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 29453517; Invitae). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 842 of the NPC1 protein (p.Phe842Leu). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004587367 | SCV005076523 | likely pathogenic | Niemann-Pick disease, type C | 2024-04-25 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.2526T>A (p.Phe842Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251120 control chromosomes. c.2526T>A has been reported in the literature in individuals affected with Niemann-Pick Disease (e.g., Fu_2022, Rodriguez_2021, Liang_2024). These data indicate that the variant may be associated with disease. Variants at the same codon, c.2524T>C, p.Phe842Leu and c.2525T>C, p.Phe842Ser, have been determined to be pathogenic/likely pathogenic in ClinVar, suggesting that this residue is clinically significant. The following publications have been ascertained in the context of this evaluation (PMID: 36307859, 38131230, 34296265). ClinVar contains an entry for this variant (Variation ID: 1932106). Based on the evidence outlined above, the variant was classified as likely pathogenic. |