ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1947+8G>C (rs66620415)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078471 SCV000110327 benign not specified 2015-09-22 criteria provided, single submitter clinical testing
Invitae RCV000528609 SCV000650836 likely benign Niemann-Pick disease type C1 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000528609 SCV001284598 uncertain significance Niemann-Pick disease type C1 2017-05-30 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV000078471 SCV001362184 benign not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: NPC1 c.1947+8G>C 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. 5/5 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 0.00078 in 240878 control chromosomes, predominantly at a frequency of 0.0032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.15 fold of 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 a benign polymorphism found primarily in populations of Latino origin. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign and benign. Based on the evidence outlined above, the variant was classified as benign.

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