Submissions for variant NM_001360.3(DHCR7):c.730G>A (p.Gly244Arg)

dbSNP: rs121909764

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007183	SCV000941238	pathogenic	Smith-Lemli-Opitz syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 244 of the DHCR7 protein (p.Gly244Arg). This variant is present in population databases (rs121909764, gnomAD 0.02%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9683613, 12270273, 12818773, 23293579). ClinVar contains an entry for this variant (Variation ID: 6781). 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	RCV000007183	SCV001163701	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001804715	SCV002051646	likely pathogenic	not provided	2021-03-16	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate
3billion, Medical Genetics	RCV000007183	SCV002059016	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006781, PMID:9683613, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.972, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Smith-Lemli-Opitz syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV001804715	SCV004701139	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	DHCR7: PM3:Strong, PM2, PP3
Fulgent Genetics, Fulgent Genetics	RCV000007183	SCV005629862	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-06-17	criteria provided, single submitter	clinical testing
OMIM	RCV000007183	SCV000027379	pathogenic	Smith-Lemli-Opitz syndrome	1998-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000007183	SCV002093030	pathogenic	Smith-Lemli-Opitz syndrome	2020-12-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748505	SCV005361263	pathogenic	DHCR7-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The DHCR7 c.730G>A variant is predicted to result in the amino acid substitution p.Gly244Arg. This variant has been reported in the compound heterozygous state in several individuals with Smith-Lemli-Opitz syndrome (Waterham et al. 1998. PubMed ID: 9683613; Balogh et al. 2012. PubMed ID: 23293579; Korade et al. 2017. PubMed ID: 28972118). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.