ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.461C>T (p.Thr154Met) (rs143312232)

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Total submissions: 4
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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 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 154 of the DHCR7 protein (p.Thr154Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (rs143312232, ExAC no frequency). This variant has been reported in many individual affected with Smith-Lemli-Opitz syndrome (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). In most of these individuals, the variant co-occurred with a known pathogenic variant in DHCR7. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Integrated Genetics/Laboratory Corporation of America RCV000169290 SCV001362509 pathogenic Smith-Lemli-Opitz syndrome 2019-03-14 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 4.1e-06 in 244720 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). 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 (Wassif_2005). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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