Submissions for variant NM_000271.5(NPC1):c.1947+14G>T

gnomAD frequency: 0.01574  dbSNP: rs3745024

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078470	SCV000110326	benign	not specified	2013-03-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078470	SCV000303370	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625294	SCV000407871	benign	Niemann-Pick disease, type C1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625294	SCV000744748	benign	Niemann-Pick disease, type C1	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078470	SCV001339024	benign	not specified	2020-03-02	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1947+14G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.045 in 233216 control chromosomes in the gnomAD database, including 1029 homozygotes. The observed variant frequency is approximately 16-fold the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0028), strongly suggesting that the variant is benign. c.1947+14G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (e.g. DeCastro-Oros_2017). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000625294	SCV001717267	benign	Niemann-Pick disease, type C1	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000625294	SCV001737967	benign	Niemann-Pick disease, type C1	2021-06-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625294	SCV000745711	likely benign	Niemann-Pick disease, type C1	2016-05-10	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000078470	SCV001807816	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078470	SCV001922945	benign	not specified		no assertion criteria provided	clinical testing