Submissions for variant NM_000271.5(NPC1):c.3343G>T (p.Val1115Phe)

gnomAD frequency: 0.00268  dbSNP: rs34226296

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078481	SCV000110337	benign	not specified	2013-02-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000767035	SCV000492076	uncertain significance	not provided	2016-12-09	criteria provided, single submitter	clinical testing	The V1115F variant in the NPC1 gene has been reported previously in the heterozygous state along with another heterozygous variant (S1178G), phase unknown, in a 6 year-old male with Niemann-Pick disease type C (Rodríguez-Quiroga et al., 2015). The NHLBI ESP Exome Sequencing Project reports V1115F was observed in 34/4406 alleles (0.77%) from individuals of African-American ancestry, including one homozygous individual, indicating it may be a rare benign variant in this population. The V1115F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V1115F as a variant of uncertain significance.
Counsyl	RCV000674624	SCV000799993	uncertain significance	Niemann-Pick disease, type C1	2018-05-16	criteria provided, single submitter	clinical testing
Invitae	RCV000674624	SCV001005724	benign	Niemann-Pick disease, type C1	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674624	SCV001283366	benign	Niemann-Pick disease, type C1	2017-10-17	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Revvity Omics, Revvity	RCV000674624	SCV003816043	uncertain significance	Niemann-Pick disease, type C1	2021-03-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767035	SCV004140856	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	NPC1: BP4
PreventionGenetics, part of Exact Sciences	RCV003935016	SCV004755183	likely benign	NPC1-related disorder	2021-04-10	criteria provided, single submitter	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078481	SCV004813540	likely benign	not specified	2024-02-09	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251462 control chromosomes, predominantly at a frequency of 0.0099 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3343G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C without strong evidence of causality (Rodriguez_2015, Kubaski_2022). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25989649, 35892469). ClinVar contains an entry for this variant (Variation ID: 92712). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000767035	SCV001807285	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000767035	SCV001964769	uncertain significance	not provided		no assertion criteria provided	clinical testing