Submissions for variant NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
MGZ Medical Genetics Center	RCV002289056	SCV002581451	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-02-10	criteria provided, single submitter	clinical testing
Invitae	RCV002289056	SCV003440565	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 451 of the DHCR7 protein (p.Cys451Arg). This variant is present in population databases (rs761458977, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 31840946). 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: 1709241). 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%. This variant disrupts the p.Cys451 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003154241	SCV003842477	likely pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant in a patient in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Kalb et al., 2012); Not observed at 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: 34426522, 22211794, 31840946, 23042628)