Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669319 | SCV000794061 | uncertain significance | Niemann-Pick disease, type C1 | 2017-09-07 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000669319 | SCV002169301 | pathogenic | Niemann-Pick disease, type C1 | 2022-12-02 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 553800). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPC1 function (PMID: 10419504, 24891511). 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 disease type C (PMID: 19252935, 32138288). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs202140203, gnomAD 0.007%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 634 of the NPC1 protein (p.Tyr634Cys). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307585 | SCV002600297 | likely pathogenic | Niemann-Pick disease, type C | 2022-10-05 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.1901A>G (p.Tyr634Cys) results in a non-conservative amino acid change located in the Sterol-sensing domain (IPR000731) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251366 control chromosomes (gnomAD). c.1901A>G has been reported in at-least one individual affected with Severe Infantile Niemann-Pick Disease Type C (examples: Fancello_2009 and Dardis_2020). Multiple publications have reported experimental evidence that this variant causes a defect in cholesterol trafficking (examples: Watari_1999 and Erwood_2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |