Submissions for variant NM_001360.3(DHCR7):c.682C>T (p.Arg228Trp)

gnomAD frequency: 0.00002  dbSNP: rs775773057

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674773	SCV000800167	uncertain significance	Smith-Lemli-Opitz syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000674773	SCV000894666	uncertain significance	Smith-Lemli-Opitz syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000674773	SCV001415982	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 228 of the DHCR7 protein (p.Arg228Trp). This variant is present in population databases (rs775773057, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15776424, 22226660). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267993	SCV001446554	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282323	SCV002572334	uncertain significance	not specified	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.682C>T (p.Arg228Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251396 control chromosomes (gnomAD). c.682C>T has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Witsch-Baumgartner_2005, Quelin_2012, Lanthaler_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: two classify the variant as uncertain significance, one as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV001267993	SCV003845603	likely pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15776424, 25040602, 22226660, 23042628, 16207203)