ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.461C>T (p.Thr154Met)

dbSNP: rs143312232
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169290 SCV000220606 likely pathogenic Smith-Lemli-Opitz syndrome 2014-08-20 criteria provided, single submitter literature only
Invitae RCV000169290 SCV000630076 pathogenic Smith-Lemli-Opitz syndrome 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 154 of the DHCR7 protein (p.Thr154Met). This variant is present in population databases (rs143312232, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). ClinVar contains an entry for this variant (Variation ID: 188923). 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%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169290 SCV001163335 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169290 SCV001362509 pathogenic Smith-Lemli-Opitz syndrome 2020-09-03 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.461C>T (p.Thr154Met) 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 4e-06 in 249850 control chromosomes (gnomAD). c.461C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Wassif_2005, Jira_2001, Krakowiak_2000, Witsch-Baumgartner_2000, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated patients carrying the variant of interest along with other pathogenic variants to exhibit decreased fractional cholesterol synthesis and expression studies showed this variant results in reduced protein expression in cell line (Witsch-Baumgartner_DHCR7_AJHG_2000, Wassif_2005). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000169290 SCV002809842 pathogenic Smith-Lemli-Opitz syndrome 2021-10-13 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000169290 SCV004234310 pathogenic Smith-Lemli-Opitz syndrome 2023-03-27 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169290 SCV002093049 pathogenic Smith-Lemli-Opitz syndrome 2017-11-28 no assertion criteria provided clinical testing

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