ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.452G>A (p.Trp151Ter) (rs11555217)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079655 SCV000493271 pathogenic not provided 2016-08-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079655 SCV000610794 pathogenic not provided 2017-09-19 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414879 SCV000493056 pathogenic 2-3 toe syndactyly; Small for gestational age; Elevated 7-dehydrocholesterol; Congenital microcephaly 2013-12-20 criteria provided, single submitter clinical testing
Counsyl RCV000020436 SCV000677969 pathogenic Smith-Lemli-Opitz syndrome 2015-06-13 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000020436 SCV000236537 pathogenic Smith-Lemli-Opitz syndrome 2014-09-30 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000020436 SCV000745304 pathogenic Smith-Lemli-Opitz syndrome 2016-10-05 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000020436 SCV000733107 pathogenic Smith-Lemli-Opitz syndrome no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000020436 SCV000238434 pathogenic Smith-Lemli-Opitz syndrome 2015-05-07 no assertion criteria provided research The heterozygous variant in the DHCR7 gene (c.452G>A; p.Trp151Term) is considered pathogenic as this variant has been previously published in multiple affected individuals and is the third most common DHCR7 mutation (Correa-Cerro et al. 2013; PMID: 15670717; Witsch-Baumgartner et al. 200; PMID: 10677299; Löffler et al 2000, PMID: 11078571).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079655 SCV000231621 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000020436 SCV000611261 pathogenic Smith-Lemli-Opitz syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000079655 SCV000329333 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The W151X variant in the DHCR7 gene has been reported previously in association with Smith-Lemli-Opitz syndrome (SLOS), in affected individuals who are compound heterozygous for the W151X variant and another pathogenic variant, and has been observed in the homozygous state in a lethal form of SLOS (Fitzky et al., 1998; Correa-Cerro et al., 2005b; Loffler et al., 2000). Fibroblast cell line studies indicate that W151X underwent nonsense-mediated mRNA decay (Correa-Cerro et al., 2005b). Although not present in the homozygous state, the W151X variant is observed in 174/125,000 alleles (0.14%) from individuals of non-Finnish European background, and 210/275,382 global alleles (0.076%), in large population cohorts (Lek et al., 2016). We interpret W151X as a pathogenic variant.
GeneReviews RCV000020436 SCV000040850 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000020436 SCV000743878 pathogenic Smith-Lemli-Opitz syndrome 2017-07-28 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000020436 SCV000606907 not provided Smith-Lemli-Opitz syndrome no assertion provided phenotyping only Variant interpretted as pathogenic and reported, most reecntly, on 12/04/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Gharavi Laboratory,Columbia University RCV000079655 SCV000809163 pathogenic not provided 2018-09-16 no assertion criteria provided research
Illumina Clinical Services Laboratory,Illumina RCV000020436 SCV000373920 pathogenic Smith-Lemli-Opitz syndrome 2016-06-14 criteria provided, single submitter clinical testing The c.452G>A (p.Trp151Ter) variant is a well-described, common stop-gained variant that accounts for 6.0% of variant DHCR7 alleles (Correa-Cerro et al. 2005a; Nowaczyk et al. 2013). Across a selection of the available literature, the p.Trp151Ter variant has been identified in at least 62 patients with Smith-Lemli-Opitz syndrome, including eight in a homozygous state and 54 in a compound heterozygous state. The p.Trp151Ter variant was also identified in a heterozygous state in 39 unaffected Polish neonates (Fitzky et al. 1998; Witsch-Baumgartner et al. 2000; Krakowiak et al. 2000; Löffler et al. 2000; Witsch-Baumgartner et al. 2001; Ciara et al. 2004; Correa-Cerro et al. 2005; Ciara et al. 2006; Kolejáková et al. 2009). The p.Trp151Ter variant was absent from 80 control individuals but is reported at a frequency of 0.00116 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated an absence of protein and no enzyme activity in HEK cells transfected with the variant (Witsch-Baumgartner et al. 2000). Correa-Cerro et al. (2005b) demonstrated that the p.Trp151Ter variant undergoes nonsense mediated decay. Haplotype analysis indicates the p.Trp151Ter variant occurs on three related haplotypes and appears to have originated in southern Poland (Witsch-Baumgartner et al. 2001; Correa-Cerro et al 2005a). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Trp151Ter variant is classified as pathogenic for Smith-Lemli-Opitz syndrome.
Institute of Human Genetics,Klinikum rechts der Isar RCV000020436 SCV000680189 pathogenic Smith-Lemli-Opitz syndrome 2017-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020436 SCV000697856 pathogenic Smith-Lemli-Opitz syndrome 2016-06-25 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.452G>A (p.Trp151X) variant results in a premature termination codon, predicted to cause a absent DHCR7 protein due to nonsense mediated decay, which is known mechanisms for disease. This prediction has been confirmed by a study using DNA and RNA level analysis which showed that mRNA derived from blood leukocytes carrying the variant of interest lacks the p. Trp151 * allele (Balogh_MS_2012). This variant was found in 82/120858 control chromosomes at a frequency of 0.0006785, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). It was reported in several SLOS patients in either homozygosity or compound heterozygosity with other pathogenic DHCR7 alleles indicating pathogenicity. Moreover, several clinical diagnostic laboratories classify variant as pathogenic. The variant is one of the most common SLOS-causing mutations with prevalence amongst affected individuals ranging from 2.3% to 50% deepening on the population studied. Taken together, this variant is classified as pathogenic.
Invitae RCV000020436 SCV000834937 pathogenic Smith-Lemli-Opitz syndrome 2019-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp151*) in the DHCR7 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs11555217, ExAC 0.1%). This variant has been reported in families and individuals affected with Smith-Lemli-Opitz syndrome (PMID: 9653161, 11078571, 15521979, 19390132) and is one of the most common variants associated with disease in individuals of European descent (PMID: 11175299, 16497572, 17965227). ClinVar contains an entry for this variant (Variation ID: 21273). Loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000020436 SCV000245598 pathogenic Smith-Lemli-Opitz syndrome 2014-11-25 criteria provided, single submitter clinical testing The p.Trp151X (NM_001360.2 c.452G>A) variant in DHCR7 has been reported in sever al individuals with Smith-Lemli-Opitz syndrome. Most of these individuals were c ompound heterozygous for the variant (Fitzky 1998, Correa-Cerro 2005). This vari ant has also been reported in ClinVar (Variation ID#21273), as pathogenic by mul tiple laboratories. It has been identified in 0.13% (174/125,000) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs11555217). Although this variant has been seen in the general p opulation, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at posi tion 151 which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the DHCR7 gene is associated with Smith-Lemli-Opitz syndrome . In summary, this variant meets our criteria to be classified as pathogenic f or Smith-Lemli-Opitz syndrome in an autosomal recessive manner based on its occu rrence in individuals with this disease and a predicted null effect.

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