ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.292C>T (p.Gln98Ter) (rs104886039)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169020 SCV000220166 likely pathogenic Smith-Lemli-Opitz syndrome 2014-03-14 criteria provided, single submitter literature only
GeneDx RCV000489856 SCV000576842 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing The Q98X nonsense variant in the DHCR7 gene has been reported multiple times previously in association with Smith-Lemli-Optiz syndrome (SLOS) (Witsch-Baumgartner et al., 2005; Bianconi et al., 2011; Lanthaler et al., 2013; Sparks et al., 2014; Eroglu et al., 2017). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q98X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the Q98X is considered a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000489856 SCV000861968 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000169020 SCV000893243 pathogenic Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169020 SCV000919259 pathogenic Smith-Lemli-Opitz syndrome 2018-04-27 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.292C>T (p.Gln98X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was observed with an allele frequency of 3.3e-05 in 274916 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (3.3e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.292C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Cardoso_2005, Correa-Cerro_2005, Roullet_2012, Witsch-Baumgartner_2005, Lanthaler_2013, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169020 SCV001163342 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Invitae RCV000169020 SCV001217828 pathogenic Smith-Lemli-Opitz syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln98*) in the DHCR7 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104886039, ExAC 0.01%). This variant has been observed in individuals with Smith Lemli Opitz syndrome (PMID: 15776424, 22929031,15979035, 15805162). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188723). Loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). For these reasons, this variant has been classified as Pathogenic.

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