ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs769218623
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Total submissions: 5
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000670698 SCV002231188 pathogenic Smith-Lemli-Opitz syndrome 2024-11-13 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%). 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. ClinVar contains an entry for this variant (Variation ID: 554967). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DHCR7 protein function. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000670698 SCV005629879 likely pathogenic Smith-Lemli-Opitz syndrome 2024-02-23 criteria provided, single submitter clinical testing

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