ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.1138T>C (p.Cys380Arg)

gnomAD frequency: 0.00001  dbSNP: rs373306653
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725474 SCV000337184 likely pathogenic not provided 2018-03-30 criteria provided, single submitter clinical testing
Invitae RCV000408382 SCV000945509 pathogenic Smith-Lemli-Opitz syndrome 2022-08-31 criteria provided, single submitter clinical testing 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. For these reasons, this variant has been classified as Pathogenic. 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: 9653161, 10677299, 20014133). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 284527). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 15896653, 17441222, 31395954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs373306653, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 380 of the DHCR7 protein (p.Cys380Arg).
Ambry Genetics RCV002321954 SCV002606673 pathogenic Inborn genetic diseases 2015-02-06 criteria provided, single submitter clinical testing The p.C380R pathogenic mutation (also known as c.1138T>C), located in coding exon 7 of the DHCR7 gene, results from a T to C substitution at nucleotide position 1138. The cysteine at codon 380 is replaced by arginine, an amino acid with highly dissimilar properties. This mutation was described along with a second pathogenic alteration in an infant with multiple dysplastic features, hypertension, and a biochemical diagnosis of Smith-Lemli-Opitz syndrome. However, phase (cis vs. trans) was not reported (Nowaczyk MJ, Am. J. Med. Genet. 2001 Oct; 103(3):223-5). In addition, in vitro studies demonstrated that this mutation decreases protein expression to 5% of wild type levels (Witsch-Baumgartner M, Am. J. Hum. Genet. 2000 Feb; 66(2):402-12). Another disease-causing mutation, p.C380Y has been described in the same codon. Based on the supporting evidence, p.C380R is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV000408382 SCV002812434 pathogenic Smith-Lemli-Opitz syndrome 2022-02-14 criteria provided, single submitter clinical testing
Counsyl RCV000408382 SCV000796081 likely pathogenic Smith-Lemli-Opitz syndrome 2017-12-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000408382 SCV001460488 likely pathogenic Smith-Lemli-Opitz syndrome 2020-09-16 no assertion criteria provided clinical testing

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