Submissions for variant NM_001360.3(DHCR7):c.1228G>C (p.Gly410Arg)

dbSNP: rs80338862

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001972582	SCV002238194	pathogenic	Smith-Lemli-Opitz syndrome	2023-12-01	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 410 of the DHCR7 protein (p.Gly410Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 29455191). ClinVar contains an entry for this variant (Variation ID: 1457187). 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.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 12818773, 15896653). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001972582	SCV002819559	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1228G>C (p.Gly410Arg) results in a non-conservative amino acid change in the encoded protein sequence within a transmembrane domain (Witsch-Baumgartner_2000). A known pathogenic variant affects the same nucleotide/amino acid (c.1228G>A (p.Gly410Ser), providing moderate evidence for pathogenicity. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246180 control chromosomes. c.1228G>C has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2000, Donoghue_2018), including a patient reported as compound heterozygote with a known pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001972582	SCV003922017	pathogenic	Smith-Lemli-Opitz syndrome	2021-05-07	criteria provided, single submitter	clinical testing	0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (18 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 4th cytoplamic loop of the transmembrane domain (PMID: 10677299). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a serine has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in two individuals with Smith-Lemli-Opitz syndrome (PMID: 10677299, PMID: 29455191). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces protein expression. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003418255	SCV004106763	pathogenic	DHCR7-related disorder	2023-02-01	criteria provided, single submitter	clinical testing	The DHCR7 c.1228G>C variant is predicted to result in the amino acid substitution p.Gly410Arg. This variant was reported in compound heterozygosity in one patient with clinical and biochemical features consistent with Smith-Lemli-Opitz syndrome (Patient 13, Donoghue SE et al 2018. PubMed ID: 29455191). At least another patient with Smith-Lemli-Optiz syndrome has been reported with this variant. However, it is unclear if this patient was compound heterozygous for another DHCR7 variant. This variant is located in the transmembrane domain, where a large number of missense have been reported (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). Another pathogenic substitution affecting this residue has also been reported in the literature (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299, Fitzky et al. 1998. PubMed ID: 9653161). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146621-C-G). This variant is interpreted as pathogenic.