ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1396G>A (p.Val466Met) (rs760428437)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000536496 SCV000893235 likely pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255209 SCV000321551 pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing The V466M missense variant in the DHCR7 gene has previously been reported in association with Smith-Lemli-Opitz syndrome (SLOS) in several unrelated individuals who had a second DHCR7 variant (Bianconi et al., 2011; Roullet et al., 2012). The V466M variant has also been observed multiple times with a pathogenic variant in unrelated patients referred for genetic testing at GeneDx, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). The V466M variant occurs at a position that is conserved across species, and in silico analysis predicts it is probably damaging to the protein structure/function. Therefore, we interpret V466M to be a pathogenic variant.
Invitae RCV000536496 SCV000630073 likely pathogenic Smith-Lemli-Opitz syndrome 2017-04-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 466 of the DHCR7 protein (p.Val466Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs760428437, ExAC 0.002%). This variant has been reported in individuals affected with Smith-Lemli-Opitz syndrome (PMID: 21990131, 22391996, 23042628). ClinVar contains an entry for this variant (Variation ID: 265097). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense variant that has been reported in several affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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