Submissions for variant NM_001360.3(DHCR7):c.1342G>A (p.Glu448Lys)

gnomAD frequency: 0.00003  dbSNP: rs80338864

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790762	SCV000233038	pathogenic	not provided	2013-08-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020435	SCV000697853	pathogenic	Smith-Lemli-Opitz syndrome	2017-06-30	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.1342G>A (p.Glu448Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/117588 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). The variant has been reported in numerous SLOS patients both in the homozygous and compound heterozygous state, and is known as a common disease variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000020435	SCV001163679	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020435	SCV001193970	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-12-12	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.1342G>A(E448K) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 16181459, 10995508 and 10814720. Classification of NM_001360.2(DHCR7):c.1342G>A(E448K) is based on the following criteria: This variant 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020435	SCV001229233	pathogenic	Smith-Lemli-Opitz syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 448 of the DHCR7 protein (p.Glu448Lys). This variant is present in population databases (rs80338864, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10602371, 10995508, 12270273, 12949967). ClinVar contains an entry for this variant (Variation ID: 6792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Genome-Nilou Lab	RCV000020435	SCV001810397	pathogenic	Smith-Lemli-Opitz syndrome	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000790762	SCV002513025	pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the E448K variant reduced protein stability and expression (Witsch-Baumgartner et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10602371, 10814720, 16181459, 12070263, 10995508, 12949967, 22975760, 10677299, 28166604, 27415407, 20301322, 16207203, 12270273, 34426522, 31589614)
Daryl Scott Lab, Baylor College of Medicine	RCV000020435	SCV002515294	pathogenic	Smith-Lemli-Opitz syndrome	2022-02-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020435	SCV005400476	pathogenic	Smith-Lemli-Opitz syndrome	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intra and interfamilial variable expressivity (PMIDs: 35305950, 20301322). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ERG4_ERG24 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in homozygous individuals with Smith-Lemli-Opitz syndrome (PMIDs: 10602371, 34349606). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001360.2:c.461C>G; p.(Thr154Arg)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000020435	SCV005630285	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-04-15	criteria provided, single submitter	clinical testing
OMIM	RCV000020435	SCV000027390	pathogenic	Smith-Lemli-Opitz syndrome	2003-09-15	no assertion criteria provided	literature only
GeneReviews	RCV000020435	SCV000040848	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
Natera, Inc.	RCV000020435	SCV002092994	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing