ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.725G>A (p.Arg242His) (rs80338857)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020439 SCV000677997 likely pathogenic Smith-Lemli-Opitz syndrome 2015-06-14 criteria provided, single submitter clinical testing
GeneReviews RCV000020439 SCV000040853 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000020439 SCV000697857 pathogenic Smith-Lemli-Opitz syndrome 2017-03-10 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.725G>A (p.Arg242His) variant located in the transmembrane domain involves the alteration of a conserved nucleotide and is predicted to be damaging by 5/5 in silico tools. This variant was found in 27/569654 control chromosomes (all heterozygotes) including ExAC at a frequency of 0.0000474, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant is one of twelve frequent mutations causing SmithLemliOpitz syndrome (Bianconi_2015) and is reported in at least five independent patients with SmithLemliOpitz syndrome in compound heterozygous state with another pathogenic/likely pathogenic variants (Krakowiak_2001, Jira_2001, Witsch-Baumgartner _2001, Matsumoto_2005, Wassif_2005, Li_2016). Biochemical analysis of DHC and cholesterol levels as well as enzymatic evaluation in fibroblast cells from patients with this variant is supportive of functional impairment due this variant. Another missense change at this residue p.Arg242Cys is a known pathogenic variant, further highlighting functional significance of this residue. In addition, multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000020439 SCV000829407 pathogenic Smith-Lemli-Opitz syndrome 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 242 of the DHCR7 protein (p.Arg242His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80338857, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Smith-Lemli-Opitz syndrome and combined with other DHCR7 variants in several individuals with this condition (PMID: 10995508, 11427181, 12818773, 15776424, 16044199). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 21276). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg242 amino acid residue in DHCR7 have been observed in affected individuals (PMID: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
SingHealth Duke-NUS Institute of Precision Medicine RCV000020439 SCV000853128 likely pathogenic Smith-Lemli-Opitz syndrome 2017-06-07 no assertion criteria provided curation

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