Submissions for variant NM_001360.3(DHCR7):c.521T>C (p.Phe174Ser)

gnomAD frequency: 0.00001  dbSNP: rs769218623

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670698	SCV000795588	uncertain significance	Smith-Lemli-Opitz syndrome	2017-11-09	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000670698	SCV001994827	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-10-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797780	SCV002041633	uncertain significance	not specified	2021-11-17	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.521T>C (p.Phe174Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251044 control chromosomes. c.521T>C has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Smith-Lemli-Opitz Syndrome, one of whom was reported as having a milder phenotypic presentation (example, Cardoso_2005, Tucci_2016). These data indicate that the variant may 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. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV000670698	SCV002231188	pathogenic	Smith-Lemli-Opitz syndrome	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the DHCR7 protein (p.Phe174Ser). This variant is present in population databases (rs769218623, gnomAD 0.01%). 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: 554967). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15979035, 26969503). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.