Submissions for variant NM_001360.3(DHCR7):c.906C>G (p.Phe302Leu)

dbSNP: rs80338858

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000020440	SCV000754771	pathogenic	Smith-Lemli-Opitz syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 302 of the DHCR7 protein (p.Phe302Leu). This variant is present in population databases (rs80338858, gnomAD 0.01%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome, or SLOS (PMID: 10814720, 12818773, 14981719, 22226660; Invitae). ClinVar contains an entry for this variant (Variation ID: 21277). 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: 15464432). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000020440	SCV001163697	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020440	SCV001193823	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-12-19	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.906C>G(F302L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 14981719, 10814720, 15464432, 12818773 and 14981719. Classification of NM_001360.2(DHCR7):c.906C>G(F302L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020440	SCV001338402	likely pathogenic	Smith-Lemli-Opitz syndrome	2023-02-19	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.906C>G (p.Phe302Leu) results in a non-conservative amino acid change located in the Loop 6-7 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251320 control chromosomes (gnomAD). c.906C>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Smith-Lemli-Opitz Syndrome and has been reported as the third most common DHCR7 mutation in Spanish SLOS alleles (example, Yu_2000, Nowaczyk_2004, Ginat_2004, Witsch-Baumgartner_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020440	SCV002557799	pathogenic	Smith-Lemli-Opitz syndrome	2022-06-24	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 (PMID: 35305950, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 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 Ergosterol biosynthesis ERG4_ERG24 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar, PMIDs: 10814720, 35305950). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001360.2(DHCR7):c.964-1G>C) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). The proband of this family has been analysed by an external laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002371779	SCV002688521	pathogenic	Inborn genetic diseases	2018-02-28	criteria provided, single submitter	clinical testing	The p.F302L pathogenic mutation (also known as c.906C>G), located in coding exon 6 of the DHCR7 gene, results from a C to G substitution at nucleotide position 906. This alteration has been reported in multiple individuals diagnosed with Smith-Lemli-Optiz syndrome and reportedly has a frequency of 15% in Spanish populations (Yu H et al. Hum. Mol. Genet., 2000 May;9:1385-91; Witsch-Baumgartner M et al. J. Med. Genet., 2008 Apr;45:200-9; Witsch-Baumgartner M et al. Eur. J. Hum. Genet., 2001 Jan;9:45-50; Lazarin GA et al. Genet. Med., 2013 Mar;15:178-86). The phenylalanine at codon 302 is replaced by leucine, an amino acid with highly similar properties. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000020440	SCV002793515	pathogenic	Smith-Lemli-Opitz syndrome	2021-12-15	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020440	SCV000040855	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only