ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.99-10G>A

gnomAD frequency: 0.00495  dbSNP: rs189549129
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000874722 SCV001016941 benign Smith-Lemli-Opitz syndrome 2021-12-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000874722 SCV001272047 uncertain significance Smith-Lemli-Opitz syndrome 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193585 SCV001362513 benign not specified 2019-09-19 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.99-10G>A 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 0.0017 in 207728 control chromosomes, predominantly at a frequency of 0.017 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome phenotype (0.0043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.99-10G>A in individuals affected with Smith-Lemli-Opitz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV001698674 SCV001916773 benign not provided 2019-02-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001193585 SCV002072348 likely benign not specified 2019-07-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV000874722 SCV002093080 likely benign Smith-Lemli-Opitz syndrome 2017-05-05 no assertion criteria provided clinical testing

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