ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1337G>A (p.Arg446Gln) (rs751604696)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498273 SCV000589633 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The R446Q missense variant has been reported previously in several unrelated individuals with SLOSwho also harbored a second variant in the DHCR7 gene (Ginat et al., 2004; Witsch-Baumgartner et al.,2005; Jezela-Stanek et al., 2010). The R446Q variant is not observed at a significant frequency inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). The R446Q variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. This substitution occurs at aposition that is conserved across species. In silico analysis predicts this variant is probably damaging tothe protein structure/function. Additionally, in silico analysis predicts that the c.1337 G>A variantresponsible for R446Q creates a new cryptic slice acceptor site in exon 9, downstream of the naturalsplice acceptor site in intron 8. However, in the absence of RNA/functional studies, the actual effectof this sequence change in this individual is unknown. In summary, we interpret R446Q as pathogenic.
Counsyl RCV000576656 SCV000677989 likely pathogenic Smith-Lemli-Opitz syndrome 2015-10-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716262 SCV000847101 likely pathogenic History of neurodevelopmental disorder 2017-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,2 of classification of c (below) met (2c = 1b),Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498273 SCV000854975 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000576656 SCV000893236 pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576656 SCV000917277 pathogenic Smith-Lemli-Opitz syndrome 2018-08-20 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.1337G>A (p.Arg446Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 274922 control chromosomes (gnomAD). c.1337G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Witsch-Baumgartner 2000, Ciara 2004, Sparks 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ginat 2004). The most pronounced variant effect results in <10% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000576656 SCV000930805 pathogenic Smith-Lemli-Opitz syndrome 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 446 of the DHCR7 protein (p.Arg446Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs751604696, ExAC 0.009%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with DHCR7-related conditions (PMID: 10677299, 15521979). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In addition, this variant has been observed in several other individuals and families affected with DHCR7-related conditions (PMID: 12818773, 10677299, 27513191, 12270273). ClinVar contains an entry for this variant (Variation ID: 431994). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.