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

gnomAD frequency: 0.00003  dbSNP: rs80338864

Total submissions: 11

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.
Invitae	RCV000020435	SCV001229233	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-17	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). 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.
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
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