ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1947+14G>T (rs3745024)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078470 SCV000110326 benign not specified 2013-03-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000078470 SCV000303370 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625294 SCV000744748 benign Niemann-Pick disease type C1 2015-09-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000625294 SCV000745711 likely benign Niemann-Pick disease type C1 2016-05-10 no assertion criteria provided clinical testing

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