Submissions for variant NM_000271.5(NPC1):c.1672G>T (p.Ala558Ser)

gnomAD frequency: 0.00003  dbSNP: rs201156397

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001127620	SCV001286949	uncertain significance	Niemann-Pick disease, type C1	2017-09-14	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001127620	SCV003443335	likely pathogenic	Niemann-Pick disease, type C1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the NPC1 protein (p.Ala558Ser). This variant is present in population databases (rs201156397, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease type C (PMID: 24386122). ClinVar contains an entry for this variant (Variation ID: 891970). 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%. This variant disrupts the p.Ala558 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22269206, 23427322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.