ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.461C>G (p.Thr154Arg) (rs143312232)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718057 SCV000848918 uncertain significance History of neurodevelopmental disorder 2017-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Counsyl RCV000179381 SCV000678157 likely pathogenic Smith-Lemli-Opitz syndrome 2017-02-24 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000179381 SCV000536765 likely pathogenic Smith-Lemli-Opitz syndrome 2016-04-27 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790776 SCV000231620 likely pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000179381 SCV000915553 likely pathogenic Smith-Lemli-Opitz syndrome 2018-08-16 criteria provided, single submitter clinical testing The DHCR7 c.461C>G (p.Thr154Arg) missense variant has been reported in at least four studies in which it is found in a total of four patients with either diagnosed or suspected Smith-Lemli-Opitz syndrome. The variant was present in three patients in a compound heterozygous state and in one patient in a heterozygous state, in whom it is not clear if a second variant was present (Witsch-Baumgartner et al. 2001; Correa-Cerro et al. 2005; Scalco et al. 2005; Haas et al. 2007). The p.Thr154Arg variant was also identified in a heterozygous state in six unaffected individuals in a large cohort undergoing routine carrier screening using next generation sequencing (Lazarin et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Thr154Arg variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000179381 SCV000953377 pathogenic Smith-Lemli-Opitz syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 154 of the DHCR7 protein (p.Thr154Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs143312232, ExAC 0.01%). This variant has been observed in several individuals affected with DHCR7-related conditions (PMID: 15952211, 15805162, 20694756, 17237122). ClinVar contains an entry for this variant (Variation ID: 166988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Thr154 amino acid residue in DHCR7 have been observed in affected individuals (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.