Submissions for variant NM_001360.3(DHCR7):c.841G>A (p.Val281Met)

gnomAD frequency: 0.00001  dbSNP: rs398123607

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079660	SCV000232613	pathogenic	not provided	2012-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000079660	SCV000321548	likely pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10677299, 27401223, 14981719, 28250423, 22438180, 17441222)
Invitae	RCV000180218	SCV000754770	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 281 of the DHCR7 protein (p.Val281Met). This variant is present in population databases (rs398123607, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Smith–Lemli–Opitz syndrome and elevated serum 7-dehydrocholesterol (PMID: 10677299, 14981719, 17441222, 27401223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93724). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624268	SCV000849786	pathogenic	Inborn genetic diseases	2017-03-27	criteria provided, single submitter	clinical testing	The p.V281M pathogenic mutation (also known as c.841G>A), located in coding exon 6 of the DHCR7 gene, results from a G to A substitution at nucleotide position 841. The valine at codon 281 is replaced by methionine, an amino acid with highly similar properties. In vitro studies have shown this mutation results in protein expression and levels less than 10% of wild-type (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12). This mutation has been reported in a patient with a diagnosis of Smith-Lemli-Opitz syndrome, as determined by clinical and biochemical findings, including decreased cholesterol and elevated levels of 7-dehydrocholesterol (Nowaczyk MJ et al. Am. J. Med. Genet. A, 2004 Mar;125A:173-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, 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	2023-10-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180218	SCV001448550	pathogenic	Smith-Lemli-Opitz syndrome	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.841G>A (p.Val281Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250306 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.0001 vs 0.0043), allowing no conclusion about variant significance. c.841G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example: Nowaczyk_2012, Witsch-Baumgartner_2000). Many of these patients had a mild phenotype. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000180218	SCV002024076	likely pathogenic	Smith-Lemli-Opitz syndrome	2020-04-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000079660	SCV002064489	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DHCR7 gene demonstrated a sequence change, c.841G>A, in exon 8 that results in an amino acid change, p.Val281Met. This sequence change has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al., 2000; Boland et al., 2016; Nowalczyk et al., 2004; Waye et al., 2007). This sequence change has been described in the gnomaD database with a low population frequency of 0.01% (dbSNP rs398123607). The p.Val281Met change affects a highly conserved amino acid residue located in a domain of the DHCR7 protein that is known to be functional. The p.Val281Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
PreventionGenetics, part of Exact Sciences	RCV003935034	SCV004754998	pathogenic	DHCR7-related disorder	2023-11-01	criteria provided, single submitter	clinical testing	The DHCR7 c.841G>A variant is predicted to result in the amino acid substitution p.Val281Met. This variant has been reported in the compound heterozygous state in many individuals with autosomal recessive Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Waye et al. 2007. PubMed ID: 17441222; Nowaczyk et al. 2012. PubMed ID: 22438180). This variant was also reported in a patient from an autism cohort (Table S2 in Saskin et al 2017. PubMed ID: 28250423). This variant is reported in 0.064% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic.
Counsyl	RCV000180218	SCV000678087	likely pathogenic	Smith-Lemli-Opitz syndrome	2018-09-26	no assertion criteria provided	clinical testing