Submissions for variant NM_001360.3(DHCR7):c.570C>T (p.Ala190=)

gnomAD frequency: 0.01097  dbSNP: rs74909468

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000390465	SCV000373919	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000428094	SCV000512801	benign	not specified	2016-01-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000390465	SCV000754775	benign	Smith-Lemli-Opitz syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311413	SCV000847344	benign	Inborn genetic diseases	2016-03-16	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428094	SCV000919260	likely benign	not specified	2017-09-11	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.570C>T (p.Ala190Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 389/121388 control chromosomes (5 homozygotes) at a frequency of 0.0032046 and in gnomAD in 941/276256 control chromosomes (15 homozygotes) at a frequency of 0.003406, which do not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). One clinical diagnostic laboratory classified this variant as uncertain significance and a second one classified it as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000390465	SCV001159636	benign	Smith-Lemli-Opitz syndrome	2018-10-29	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004703607	SCV005218427	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000390465	SCV002093040	benign	Smith-Lemli-Opitz syndrome	2017-05-05	no assertion criteria provided	clinical testing