Submissions for variant NM_000271.5(NPC1):c.3548G>A (p.Arg1183His)

gnomAD frequency: 0.00047  dbSNP: rs148035987

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000729875	SCV000857568	uncertain significance	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793551	SCV000932909	uncertain significance	Niemann-Pick disease, type C1	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1183 of the NPC1 protein (p.Arg1183His). This variant is present in population databases (rs148035987, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 594562). 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. 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.
Illumina Laboratory Services, Illumina	RCV000793551	SCV001282154	uncertain significance	Niemann-Pick disease, type C1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000729875	SCV002015739	uncertain significance	not provided	2024-05-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Kandakatla2014[Article])
Fulgent Genetics, Fulgent Genetics	RCV000793551	SCV002780385	uncertain significance	Niemann-Pick disease, type C1	2021-12-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000793551	SCV001453828	uncertain significance	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003908034	SCV004727436	likely benign	NPC1-related disorder	2022-02-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).