Submissions for variant NM_001360.3(DHCR7):c.139C>T (p.Leu47=)

gnomAD frequency: 0.00027  dbSNP: rs140721259

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000279800	SCV000335785	uncertain significance	not provided	2015-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314006	SCV000848849	likely benign	Inborn genetic diseases	2017-01-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001483712	SCV001688114	likely benign	Smith-Lemli-Opitz syndrome	2024-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532990	SCV001748825	likely benign	not specified	2021-06-23	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.139C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing while predicting the disruption of ESE binding sites. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.9e-05 in 236214 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (5.9e-05 vs 0.0043), allowing no conclusion about variant significance. c.139C>T has been reported in the literature as a polymorphism and/or non pathogenic variant in individuals affected with Smith-Lemli-Opitz Syndrome (example, Witsch-Baumgartner_2001, Jira_2003, Waterham_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. 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 (VUS, n=1; likely benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000279800	SCV001981889	likely benign	not provided	2021-01-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001483712	SCV002093076	likely benign	Smith-Lemli-Opitz syndrome	2020-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003909950	SCV004725990	likely benign	DHCR7-related disorder	2021-06-14	no assertion criteria provided	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).