ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Invitae RCV000180218 SCV000754770 pathogenic Smith-Lemli-Opitz syndrome 2019-11-15 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.
Ambry Genetics RCV000718922 SCV000849786 pathogenic History of neurodevelopmental disorder 2017-03-27 criteria provided, single submitter clinical testing 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
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.
Baylor Genetics RCV000180218 SCV001163699 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Counsyl RCV000180218 SCV000678087 likely pathogenic Smith-Lemli-Opitz syndrome 2018-09-26 no assertion criteria provided clinical testing

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