Submissions for variant NM_001360.3(DHCR7):c.1210C>T (p.Arg404Cys)

gnomAD frequency: 0.00006  dbSNP: rs61757582

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723830	SCV000700667	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000007190	SCV000893238	pathogenic	Smith-Lemli-Opitz syndrome	2021-07-12	criteria provided, single submitter	clinical testing
Invitae	RCV000007190	SCV000938503	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 404 of the DHCR7 protein (p.Arg404Cys). This variant is present in population databases (rs61757582, gnomAD 0.009%). This missense change has been observed in individuals with Smith–Lemli–Opitz syndrome (PMID: 9653161, 10677299, 12818773, 15896653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6788). 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%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000007190	SCV001163686	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007190	SCV001193936	pathogenic	Smith-Lemli-Opitz syndrome	2019-12-04	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.1210C>T(R404C) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and can be associated with mild to severe forms of this disease. Sources cited for classification include the following: PMID 10677299, 22438180, 15954111, and 22438180. Classification of NM_001360.2(DHCR7):c.1210C>T(R404C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007190	SCV001361497	pathogenic	Smith-Lemli-Opitz syndrome	2020-08-20	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1210C>T (p.Arg404Cys) results in a non-conservative amino acid change located in the Ergosterol biosynthesis ERG4/ERG24 domain (IPR001171) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 241396 control chromosomes. c.1210C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Fitzky_1998, Witsch-Baumgartner_2000). 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. Both publications reported that expression of p.Arg404Cys in human cell line resulted in similar transcript but reduced protein expression as compared with wildtype (<10%, Fitzky_1998, Witsch-Baumgartner_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001266513	SCV001444688	pathogenic	Inborn genetic diseases	2020-02-13	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.1210C>T (p.R404C) alteration is located in exon 9 (coding exon 7) of the DHCR7 gene. This alteration results from a C to T substitution at nucleotide position 1210, causing the arginine (R) at amino acid position 404 to be replaced by a cysteine (C). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1210C>T alteration was observed in 0.0044% (12/272,768) total alleles studied. No homozygotes were reported. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in multiple patients with Smith Lemli Opitz syndrome (SLOS). The alteration was first reported in a consanguineous family of French origin from Louisiana and was considered a French founder mutation (Fitzky, 1998). Heterologous expression of p.R404C in a human cell line decreased expression of the DHCR7 protein by more than 90% (Fitzky, 1998). Two patients were found to be homozygous for the p.R404C alteration, one died at 6 weeks of age and the other died at one year of age, and another baby with severe SLOS was compound heterozygous for this alteration and IVS8-1G>C (Witsch-Baumgartner, 2000). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R404 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.R404C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000723830	SCV001811899	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing	In vitro expression studies in a human cell line demonstrated that R404C is associated with reduced protein expression (Fitzky, et al, 1998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15896653, 28250423, 22975760, 29455191, 20301322, 31589614, 33578785, 32058062, 34447666, 28166604, 33836803, 34427008, 9653161)
PreventionGenetics, part of Exact Sciences	RCV003407290	SCV004108580	pathogenic	DHCR7-related disorder	2023-07-09	criteria provided, single submitter	clinical testing	The DHCR7 c.1210C>T variant is predicted to result in the amino acid substitution p.Arg404Cys. This variant has been documented to be causative for autosomal recessive Smith-Lemli-Optiz Syndrome (Fitzky et al. 1998. PubMed ID: 9653161; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). It is reported in 0.0083% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146639-G-A). It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6788). This variant is interpreted as pathogenic.
OMIM	RCV000007190	SCV000027386	pathogenic	Smith-Lemli-Opitz syndrome	2001-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000007190	SCV000040846	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723830	SCV002035063	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723830	SCV002037485	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000007190	SCV002093003	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing