Submissions for variant NM_000271.5(NPC1):c.2974G>C (p.Gly992Arg)

gnomAD frequency: 0.00006  dbSNP: rs80358254

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000003103	SCV000220328	likely pathogenic	Niemann-Pick disease, type C1	2014-05-19	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000489250	SCV000331815	pathogenic	not provided	2017-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000489250	SCV000576990	pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23821321, 23773996, 15596783, 16098014, 19307542, 28710748, 26984608, 25537619, 16126423, 24570279, 25349751, 20718790, 19609713, 19013089, 12205649, 11479732, 12955717, 26790753, 32138288, 34426522, 33360098, 31589614, 11333381, 34830064)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590044	SCV000696418	pathogenic	Niemann-Pick disease, type C	2017-04-26	criteria provided, single submitter	clinical testing	Variant summary: The NPC1 c.2974G>C (p.Gly992Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121558 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). This variant has been reported in NPC patients (mostly adult-onset) both as homozygote and compound heterozygote. Another variant involving the same nucleotide G2974A, causing the same amino acid change G992R, has also been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003103	SCV000934524	pathogenic	Niemann-Pick disease, type C1	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 992 of the NPC1 protein (p.Gly992Arg). This variant is present in population databases (rs80358254, gnomAD 0.02%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 11333381, 16126423, 26984608). ClinVar contains an entry for this variant (Variation ID: 2969). 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.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9634529, 12955717, 16126423, 20718790). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000489250	SCV001371367	likely pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000489250	SCV001712931	pathogenic	not provided	2019-05-21	criteria provided, single submitter	clinical testing	PS1, PS4, PM1, PM2, PM5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003103	SCV002767264	pathogenic	Niemann-Pick disease, type C1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Niemann-Pick disease type C1 (MIM# 257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - This variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). Additionally, an alternative nucleotide change (G>A) resulting in the same amino acid substitution is also present in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a region within the cysteine-rich luminal loop where many missense variants have been reported (PMID: 16126423, PMID: 11333381). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two different variants in the same codon resulting in a changes to an alanine and a tryptophan have also been reported as pathogenic in patients with Niemann-Pick type C disease (ClinVar, PMID: 16126423, PMID: 32138288). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with Niemann-Pick type C disease. Additionally, another variant involving an alternative nucleotide change (G>A) that causes the same amino acid change has also been reported as pathogenic in patients with Niemann-Pick type C disease (ClinVar, PMID: 11333381, PMID: 32138288). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000003103	SCV000023261	pathogenic	Niemann-Pick disease, type C1	2004-12-14	no assertion criteria provided	literature only
GeneReviews	RCV000003103	SCV000040573	not provided	Niemann-Pick disease, type C1		no assertion provided	literature only
Natera, Inc.	RCV000003103	SCV002095176	pathogenic	Niemann-Pick disease, type C1	2020-07-23	no assertion criteria provided	clinical testing