Submissions for variant NM_001360.3(DHCR7):c.739G>A (p.Ala247Thr)

dbSNP: rs767031102

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001387184	SCV001587747	pathogenic	Smith-Lemli-Opitz syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ala247 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 10995508). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1074014). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs767031102, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 247 of the DHCR7 protein (p.Ala247Thr). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331145	SCV004038282	uncertain significance	not specified	2023-08-01	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.739G>A (p.Ala247Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251312 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.739G>A in individuals affected with Smith-Lemli-Opitz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, a different substitution affecting this codon has been reported (c.740C>T [p.Ala247Val]; HGMD: CM980549, ClinVar: 280065), suggesting this residue may of clinical significance. One ClinVar submitter has assessed the variant since 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.