Submissions for variant NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr)

gnomAD frequency: 0.00001  dbSNP: rs779709646

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169472	SCV000220916	likely pathogenic	Smith-Lemli-Opitz syndrome	2014-11-25	criteria provided, single submitter	literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000169472	SCV000803782	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-10-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169472	SCV001163687	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV000169472	SCV001225668	pathogenic	Smith-Lemli-Opitz syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 380 of the DHCR7 protein (p.Cys380Tyr). This variant is present in population databases (rs779709646, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 10677299, 15896653, 25405082). ClinVar contains an entry for this variant (Variation ID: 189069). 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%. This variant disrupts the p.Cys380 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15896653, 17441222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001171660	SCV001334463	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453569	SCV002612936	pathogenic	Inborn genetic diseases	2016-02-03	criteria provided, single submitter	clinical testing	The p.C380Y pathogenic mutation (also known as c.1139G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1139. The cysteine at codon 380 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been observed in homozygous and heterozygous states in multiple individuals with clinical and biochemical features characteristic of Smith-Lemli-Optiz syndrome (SLOS) (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12, Pappu AS, et al. J. Lipid Res. 2006; 47(12):2789-98, Bukelis I, et al. Am J Psychiatry 2007; 164(11):1655-61). In one study using an immunoreactivity assay, protein expression of this alteration was observed to be 40% of wild type levels (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12). In addition, a different mutation located at the same position, p.C380R, has been detected in individuals with SLOS, and was shown to decrease protein expression to 5% of wild type levels (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12, Nowaczyk MJ, et al. Am. J. Med. Genet. 2001; 103(3):223-5). Based on the supporting evidence, p.C380Y is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000169472	SCV002779328	pathogenic	Smith-Lemli-Opitz syndrome	2022-04-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169472	SCV002093008	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing