Submissions for variant NM_001360.3(DHCR7):c.976G>T (p.Val326Leu)

gnomAD frequency: 0.00005  dbSNP: rs80338859

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007187	SCV000697860	pathogenic	Smith-Lemli-Opitz syndrome	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.976G>T (p.Val326Leu) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. This variant was found in 5/104104 control chromosomes at a frequency of 0.000048, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Authors have also indicated the variant to be a common mutation (Ciara_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000007187	SCV000835626	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 326 of the DHCR7 protein (p.Val326Leu). This variant is present in population databases (rs80338859, gnomAD 0.005%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 9653161, 15521979, 27513191). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6785). 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 80%. Studies have shown that this missense change alters DHCR7 gene expression (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000007187	SCV000893241	pathogenic	Smith-Lemli-Opitz syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007187	SCV001163693	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007187	SCV001193943	pathogenic	Smith-Lemli-Opitz syndrome	2019-12-20	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.976G>T(V326L) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with moderate or mild forms of the disease. Sources cited for classification include the following: PMID 15521979. Classification of NM_001360.2(DHCR7):c.976G>T(V326L) 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.
GeneDx	RCV001550331	SCV001770642	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as the DHCR7 protein expression was significantly reduced in cells expressing the V326L variant compared to wildype, suggesting the variant impairs protein stability due to misfolding or defective transports (Fitzky et al., 1998); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9653161, 22975760, 26887953, 11175299, 32257592, 34426522, 31589614, 34308104, 31840946, 33836803, 33890232)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000007187	SCV002061512	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-08-09	criteria provided, single submitter	clinical testing	PS3, PM2, PM3
OMIM	RCV000007187	SCV000027383	pathogenic	Smith-Lemli-Opitz syndrome	2004-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000007187	SCV000040856	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
Natera, Inc.	RCV000007187	SCV002093017	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing