Submissions for variant NM_001360.3(DHCR7):c.655T>G (p.Tyr219Asp)

gnomAD frequency: 0.00001  dbSNP: rs779896782

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493359	SCV000582971	likely pathogenic	not provided	2021-04-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 18249054, 23042628, 20556518)
Counsyl	RCV000668765	SCV000793417	uncertain significance	Smith-Lemli-Opitz syndrome	2017-08-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000668765	SCV001163330	likely pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668765	SCV002238197	pathogenic	Smith-Lemli-Opitz syndrome	2023-06-15	criteria provided, single submitter	clinical testing	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: 430220). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 18249054). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs779896782, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 219 of the DHCR7 protein (p.Tyr219Asp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271516	SCV002555718	uncertain significance	not specified	2022-06-07	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.655T>G (p.Tyr219Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.655T>G has been reported in the literature in an individual affected with Smith-Lemli-Opitz Syndrome in the compound heterozygous state (Jezela-Stanek_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000668765	SCV005629870	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-06-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668765	SCV001460491	likely pathogenic	Smith-Lemli-Opitz syndrome	2020-09-16	no assertion criteria provided	clinical testing