Submissions for variant NM_001360.3(DHCR7):c.440G>A (p.Gly147Asp)

gnomAD frequency: 0.00009  dbSNP: rs777425801

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421810	SCV000521158	likely pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	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: 21706511, 10995508, 28250423, 10677299, 31980526, 29770994, 12818773, 27401223, 15896653)
Counsyl	RCV000665794	SCV000789970	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV000665794	SCV000946087	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 147 of the DHCR7 protein (p.Gly147Asp). This variant is present in population databases (rs777425801, gnomAD 0.02%). This missense change has been observed in individuals with Smith–Lemli–Opitz syndrome (PMID: 10995508, 12818773). ClinVar contains an entry for this variant (Variation ID: 381657). 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.
Baylor Genetics	RCV000665794	SCV001163338	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665794	SCV001361500	pathogenic	Smith-Lemli-Opitz syndrome	2020-12-23	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.440G>A (p.Gly147Asp) 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 8.8e-05 in 248932 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (8.8e-05 vs 0.0043), allowing no conclusion about variant significance. c.440G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Witsch-Baumgartner_2000, Krakowiak_2000, Goldenberg_2003, Petracchi_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000665794	SCV002024075	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000665794	SCV002790135	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-01-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000665794	SCV001460495	likely pathogenic	Smith-Lemli-Opitz syndrome	2020-09-16	no assertion criteria provided	clinical testing