Submissions for variant NM_001360.3(DHCR7):c.1222T>C (p.Tyr408His)

gnomAD frequency: 0.00001  dbSNP: rs1046560765

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667912	SCV000792436	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-06-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000667912	SCV001163684	likely pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV000667912	SCV002145593	pathogenic	Smith-Lemli-Opitz syndrome	2022-08-31	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. 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: 552616). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 10995508, 12818773, 15896653). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 408 of the DHCR7 protein (p.Tyr408His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667912	SCV003800881	likely pathogenic	Smith-Lemli-Opitz syndrome	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1222T>C (p.Tyr408His) results in a conservative amino acid change located in the 4th Cytoplasmic loop/TM domain (Witsch-Baumgartner_2000) of 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 4.1e-06 in 246792 control chromosomes. c.1222T>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Smith-Lemli-Opitz Syndrome (example, PMID: 10995508, 23918729, 22438180, 33890232, 15896653, 15954111, 10677299). 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. Two 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003327443	SCV004034356	likely pathogenic	not provided	2023-09-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed multiple times with a second DHCR7 variant in unrelated patients with Smithh-Lemli-Opitz syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Krakowiak et al., 2000; Waye et al., 2005; Lee et al., 2013); This variant is associated with the following publications: (PMID: 11942534, 12818773, 28166604, 34308104, 11767235, 11001806, 15954111, 22438180, 23042628, 10995508, 10677299, 23918729, 12914579, 11111101, 33890232, 18076100, 15896653)