ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.841G>A (p.Val281Met) (rs398123607)

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
Ambry Genetics RCV000624268 SCV000741701 uncertain significance Inborn genetic diseases 2016-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Ambry Genetics RCV000718922 SCV000849786 pathogenic History of neurodevelopmental disorder 2017-03-27 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,Deficient protein function by in vitro/ex vivo assay,Other strong data supporting pathogenic classification
Counsyl RCV000180218 SCV000678087 likely pathogenic Smith-Lemli-Opitz syndrome 2016-08-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079660 SCV000232613 pathogenic not provided 2012-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000079660 SCV000321548 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The V281M variant in the DHCR7 gene has been reported previously in combination with another pathogenic DHCR7 variant in several individuals with a biochemically confirmed diagnosis of Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al., 2000; Nowaczyk et al., 2004; Solomon et al., 2015). The V281M variant is observed in 23/33,562 (0.07%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The V281M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret V281M as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000180218 SCV000915551 pathogenic Smith-Lemli-Opitz syndrome 2018-08-14 criteria provided, single submitter clinical testing The DHCR7 c.841G>A (p.Val281Met) missense variant has been reported in a compound heterozygous state in nine individuals affected with Smith-Lemli-Opitz syndrome (SLOS) (Witsch-Baumgartner et al. 2000; Nowaczyk et al. 2004; Nowaczyk et al. 2012; Solomon et al. 2015). In eight of these individuals, the variant was identified in trans with a second missense variant, including a previously described founder variant. These individuals exhibited a mild or moderate-to-severe phenotype. The p.Val281Met variant was also found in trans with a null allele in one individual who died two days after birth and displayed syndactyly, microcephaly, and hypotonia (Solomon et al. 2015). This individual's healthy father was a heterozygous carrier of the p.Val281Met variant, while the healthy mother was heterozygous for the null allele. Control data are unavailable for this variant, which is reported at a frequency of 0.000685 in the Latino population of the Genome Aggregation Database. Based on the evidence, p.Val281Met variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000180218 SCV000754770 pathogenic Smith-Lemli-Opitz syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 281 of the DHCR7 protein (p.Val281Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs398123607, ExAC 0.04%). This variant has been reported to be compound heterozygous in multiple individuals with clinical features of Smith–Lemli–Opitz syndrome (PMID: 27401223, 14981719, 17441222, Invitae), and in at least two individuals with elevated serum 7-dehydrocholesterol (PMID: 10677299, 17441222). ClinVar contains an entry for this variant (Variation ID: 93724). 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"). 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.