Submissions for variant NM_001360.3(DHCR7):c.1349_1350delinsTG (p.Arg450Leu)

dbSNP: rs1591107040

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000808556	SCV000948666	pathogenic	Smith-Lemli-Opitz syndrome	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 450 of the DHCR7 protein (p.Arg450Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). ClinVar contains an entry for this variant (Variation ID: 652894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9714006, 10405455, 10677299). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001560504	SCV001782932	pathogenic	not provided	2020-10-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; However, a different variant (c.1349G>T) resulting in the same missense alteration (p.R450L) have been reported in association with Smith-Lemli-Optiz syndrome (Witsch-Baumgartner et al., 2000; Correra-Cerro et al., 2005); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10677299, 16181459, 15805162, 10405455)
Ambry Genetics	RCV002381791	SCV002690293	pathogenic	Inborn genetic diseases	2020-07-28	criteria provided, single submitter	clinical testing	The c.1349_1350delGCinsTG pathogenic mutation, located in coding exon 7 of the DHCR7 gene, results from an in-frame deletion of GC and insertion of TG at nucleotide positions 1349 to 1350. This results in the substitution of the arginine residue for a leucine residue at codon 450, an amino acid with dissimilar properties. This alteration has been detected in conjunction with other known pathogenic mutations in DHCR7 (c.964-1G>C, p.R242C, p.Q95*/p.Q98*) in several individuals with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305; Chang S et al. Mol Genet Metab Rep, 2014;1:431-442; Anstey AV et al. Br. J. Dermatol., 2005 Oct;153:774-9; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Eroglu Y et al. Am. J. Med. Genet. A, 2017 Aug;173:2097-2100). In addition, several functional studies showed that this alteration resulted in significantly reduced enzymatic activity when expressed in cell lines (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV001560504	SCV004010100	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	DHCR7: PS1, PM2, PM3, PP4, PS3:Supporting