ClinVar Miner

Submissions for variant NM_018486.3(HDAC8):c.356C>T (p.Thr119Met)

dbSNP: rs587779380
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000077779 SCV001362109 pathogenic Cornelia de Lange syndrome 5 2019-12-19 criteria provided, single submitter clinical testing Variant summary: HDAC8 c.356C>T (p.Thr119Met) results in a non-conservative amino acid change located in the Histone deacetylase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182900 control chromosomes (gnomAD). c.356C>T has been reported in the literature in individuals affected with Cornelia de Lange syndrome 5 (Yuan_2015, Salzberg_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar (last evaluated in 2013 and 2014, respectively). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000077779 SCV001407645 pathogenic Cornelia de Lange syndrome 5 2022-04-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 119 of the HDAC8 protein (p.Thr119Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome or Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 24375697, 25574841). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 92043). 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 HDAC8 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000077779 SCV001521187 pathogenic Cornelia de Lange syndrome 5 2019-11-19 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Centogene AG - the Rare Disease Company RCV000077779 SCV002059697 pathogenic Cornelia de Lange syndrome 5 2021-10-27 criteria provided, single submitter clinical testing
Mendelics RCV000077779 SCV002516538 pathogenic Cornelia de Lange syndrome 5 2022-05-04 criteria provided, single submitter clinical testing
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University RCV000077779 SCV000109590 pathogenic Cornelia de Lange syndrome 5 2013-12-18 no assertion criteria provided clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000077779 SCV000195848 pathogenic Cornelia de Lange syndrome 5 2014-12-02 no assertion criteria provided research

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