Submissions for variant NM_000271.5(NPC1):c.180G>T (p.Gln60His)

gnomAD frequency: 0.00034  dbSNP: rs145666943

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728354	SCV000855913	uncertain significance	not provided	2017-07-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125610	SCV001284699	uncertain significance	Niemann-Pick disease, type C1	2017-04-28	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.
GeneDx	RCV000728354	SCV001819373	uncertain significance	not provided	2021-01-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31635081, 24386122, 30556376)
Invitae	RCV001125610	SCV003254826	uncertain significance	Niemann-Pick disease, type C1	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 60 of the NPC1 protein (p.Gln60His). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs145666943, gnomAD 0.07%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 24386122). ClinVar contains an entry for this variant (Variation ID: 593342). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NPC1 function (PMID: 31635081). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000728354	SCV004140868	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	NPC1: BP5
Mayo Clinic Laboratories, Mayo Clinic	RCV000728354	SCV004224469	uncertain significance	not provided	2022-05-03	criteria provided, single submitter	clinical testing	PP4, PM2, PM3
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000728354	SCV001809110	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000728354	SCV001958998	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001125610	SCV002095233	uncertain significance	Niemann-Pick disease, type C1	2020-01-14	no assertion criteria provided	clinical testing