Submissions for variant NM_000271.5(NPC1):c.3217G>A (p.Gly1073Ser)

gnomAD frequency: 0.00105  dbSNP: rs141440861

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000243260	SCV000341094	likely benign	not specified	2016-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081451	SCV000826236	likely benign	Niemann-Pick disease, type C1	2025-01-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000697615	SCV001151486	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	NPC1: BP4
Illumina Laboratory Services, Illumina	RCV001081451	SCV001283367	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000697615	SCV002009282	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000697615	SCV005080865	uncertain significance	not provided	2023-09-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000243260	SCV005185281	likely benign	not specified	2024-05-09	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3217G>A (p.Gly1073Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251344 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.0027), however, in certain subpopulations the variant was found with even higher frequency (e.g. in the Swedish, AF: 0.00425), suggesting that the variant is probably benign. To our knowledge, no occurrence of c.3217G>A in individuals affected with Niemann-Pick Disease Type C and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 255696). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003891841	SCV000303378	likely benign	NPC1-related disorder	2019-05-20	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).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000697615	SCV001808074	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000697615	SCV001970536	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001081451	SCV002095167	likely benign	Niemann-Pick disease, type C1	2020-01-19	no assertion criteria provided	clinical testing