Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003064506 | SCV003442585 | pathogenic | Niemann-Pick disease, type C1 | 2023-01-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 11349231, 11479732, 28105569, 31139477). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 92 of the NPC1 protein (p.Gln92Arg). |
| Neuberg Centre For Genomic Medicine, |
RCV003064506 | SCV005042808 | pathogenic | Niemann-Pick disease, type C1 | criteria provided, single submitter | clinical testing | The missense variant c.275A>G p.Gln92Arg in the NPC1 gene has been reported previously in homozygous state in individuals affected with Niemann-Pick Type C. Experimental studies have shown that this missense change affects protein function Petukh et al., 2018; Mavridou et al., 2017. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic. The amino acid Glutamine at position 92 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gln92Arg in NPC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. |