ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790776 SCV000231620 likely pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000718057 SCV000848918 pathogenic History of neurodevelopmental disorder 2020-03-02 criteria provided, single submitter clinical testing The p.T154R pathogenic mutation (also known as c.461C>G), located in coding exon 4 of the DHCR7 gene, results from a C to G substitution at nucleotide position 461. The threonine at codon 154 is replaced by arginine, an amino acid with similar properties. This mutation has been detected in four individuals with Smith-Lemli-Opitz syndrome (SLOS); three of the individuals carried another pathogenic mutation although the phase of these alterations was unknown (Witsch-Baumgartner M et al. Eur. J. Hum. Genet., 2001 Jan;9:45-50; Correa-Cerro LS et al. J. Med. Genet., 2005 Apr;42:350-7; Scalco FB et al. Am. J. Med. Genet. A, 2005 Jul;136:278-81; Haas D et al. J. Med. Genet., 2007 May;44:298-305). Based on our internal structural analysis, this mutation is predicted to be more destabilizing than nearby known pathogenic variants (Li X et al. Nature, 2015 Jan;517:104-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 2020-10-19 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.
Baylor Genetics RCV000179381 SCV001163336 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179381 SCV001554625 pathogenic Smith-Lemli-Opitz syndrome 2021-03-26 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.461C>G (p.Thr154Arg) results in a non-conservative amino acid change located in the membrane-associated helix (MAH 3, Waterham_2012) of the encoded protein sequence . Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 774648 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.461C>G has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2001, Correa-Cerro__2005, Scalco_2005, Haas_2007, Boland_2016). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue T154M has been observed in affected SLOS individuals (Witsch-Baumgartner_2001, Correa-Cerro__2005, Boland_2016), suggesting that the variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000179381 SCV001752454 likely pathogenic Smith-Lemli-Opitz syndrome 2021-06-30 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
Counsyl RCV000179381 SCV000678157 likely pathogenic Smith-Lemli-Opitz syndrome 2017-02-24 no assertion criteria provided clinical testing
GeneDx RCV000790776 SCV001803604 pathogenic not provided 2021-04-09 no assertion criteria provided clinical testing The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17237122, 15952211, 12914579, 15670717, 11241839, 11175299, 15805162, 23042628, 28166604, 29300326, 10677299, 10995508, 20694756)

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