Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000996656 | SCV001151485 | uncertain significance | not provided | 2019-05-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001805961 | SCV002050820 | likely pathogenic | Niemann-Pick disease, type C | 2021-12-08 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.3230G>A (p.Arg1077Gln) results in a conservative amino acid change located in the Endolum-loop I domain (Fancello_2009) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251198 control chromosomes (gnomAD). c.3230G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (e.g. Fancello_2009, Kumar_2016, Reunert_2016). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to exhibit an intermediate level of trafficking from the endoplasmic reticulum and to result in higher levels of cholesterol compared to wild-type in transfected cells (Pipalia_2017, Wang_2019). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV002549945 | SCV003197413 | likely pathogenic | Niemann-Pick disease, type C1 | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1077 of the NPC1 protein (p.Arg1077Gln). This variant is present in population databases (rs534280005, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 19252935, 26981555, 27550898). ClinVar contains an entry for this variant (Variation ID: 808372). 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 not expected to disrupt NPC1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects NPC1 function (PMID: 31699992). 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. |