Submissions for variant NM_001360.3(DHCR7):c.1337G>A (p.Arg446Gln)

gnomAD frequency: 0.00002  dbSNP: rs751604696

Total submissions: 9

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	RCV002311810	SCV000847101	likely pathogenic	Inborn genetic diseases	2017-10-27	criteria provided, single submitter	clinical testing	The p.R446Q variant (also known as c.1337G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1337. The arginine at codon 446 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a second DHCR7 alteration in at least five individuals with clinically and biochemically confirmed diagnoses of Smith-Lemli-Opitz syndrome (SLOS) (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Jezela-Stanek A et al. Eur J Med Genet Dec;51:124-40; Patrono C et al. Mol. Cell. Probes, 2002 Aug;16:315-8; Ciara E et al. Clin. Genet., 2004 Dec;66:517-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Eurofins Ntd Llc (ga)	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	2022-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 446 of the DHCR7 protein (p.Arg446Gln). This variant is present in population databases (rs751604696, gnomAD 0.006%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 10677299, 12270273, 12818773, 15521979, 27513191). 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: 431994). 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.
Baylor Genetics	RCV000576656	SCV001163680	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000576656	SCV002512348	pathogenic	Smith-Lemli-Opitz syndrome	2021-12-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM2 moderate, PM2, PM3 very strong, PP1 supporting, PP1, PP3 supporting