Submissions for variant NM_001360.3(DHCR7):c.1228G>A (p.Gly410Ser)

gnomAD frequency: 0.00007  dbSNP: rs80338862

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079640	SCV000233037	pathogenic	not provided	2013-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000079640	SCV000564934	pathogenic	not provided	2020-10-30	criteria provided, single submitter	clinical testing	Expression studies in a human cell line found that G410S reduced DHCR7 protein expression by greater than 90% compared to wild-type (Fitzky et al., 1998); 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: 31589614, 31840946, 31395954, 17237122, 22391996, 20301322, 27415407, 28166604, 19390132, 15952211, 22211794, 22226660, 25405082, 15013448, 9653161, 22975760, 23042628)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020434	SCV000697851	pathogenic	Smith-Lemli-Opitz syndrome	2017-05-04	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.1228G>A (p.Gly410Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.000043 (5/116304 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). In the literature, the variant has been identified in several patients with SLOS in compound heterozygous state with other pathogenic/likely pathogenic mutations as well as in homozygous state (e.g., Kolejakova_Gen Physiol Biophys_2009; Kalb_Clin Genet_2012). Cell-based functional studies have been performed that revealed a severe reduction in protein expression and enzyme activity due to the variant (Fitzky_PNAS_1998; Shim_BBRC_2004). The variant also lies at one of the transmembrane regions of the protein, where many known pathogenic mutations are located (Fitzky_PNAS_1998). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000020434	SCV000832368	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 410 of the DHCR7 protein (p.Gly410Ser). This variant is present in population databases (rs80338862, gnomAD 0.03%). This missense change has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 9653161, 12818773, 15896653). ClinVar contains an entry for this variant (Variation ID: 21272). 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). This variant disrupts the p.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been observed in individuals with DHCR7-related conditions (PMID: 10677299), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002316198	SCV000850897	pathogenic	Inborn genetic diseases	2022-11-22	criteria provided, single submitter	clinical testing	The c.1228G>A (p.G410S) alteration is located in exon 9 (coding exon 7) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 1228, causing the glycine (G) at amino acid position 410 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.007% (18/246180) total alleles studied. The highest observed frequency was 0.032% (11/34440) of Latino alleles. This alteration has been detected in both the homozygous and compound heterozygous states in multiple individuals with Smith-Lemli-Opitz syndrome (SLOS) (Schoner, 2020; Wojcik, 2019; Kalb, 2012; Haas, 2007; Boland, 2016; Kolejáková, 2009; Scalco, 2005; Babovic-Vuksanovic, 2005; Wassif, 2005; Shim, 2004; Yu, 2000; Kozak, 2000; Fitzky,1998). This amino acid position is highly conserved in available vertebrate species. In two separate functional studies, this alteration was shown to reduce DHCR7 protein expression and enzymatic activity (Fitzky, 1998; Shim, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000020434	SCV001163683	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020434	SCV001193975	pathogenic	Smith-Lemli-Opitz syndrome	2019-12-12	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.1228G>A(G410S) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 9653161, 15877207, 10896306, 10814720, 15952211, 12818773, 15896653 and 22391996. Classification of NM_001360.2(DHCR7):c.1228G>A(G410S) 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.
Revvity Omics, Revvity	RCV000020434	SCV002020378	pathogenic	Smith-Lemli-Opitz syndrome	2020-10-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000020434	SCV002782376	pathogenic	Smith-Lemli-Opitz syndrome	2021-11-18	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020434	SCV000040847	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000079640	SCV001743104	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079640	SCV001956178	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020434	SCV002092999	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing