ClinVar Miner

Submissions for variant NM_001354712.2(THRB):c.728G>A (p.Arg243Gln)

dbSNP: rs121918706
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760093 SCV000889873 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000013394 SCV002548027 pathogenic Thyroid hormone resistance, generalized, autosomal dominant 2022-05-01 criteria provided, single submitter clinical testing Variant summary: THRB c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250376 control chromosomes. c.728G>A has been reported in the literature in multiple individuals affected with Generalized Autosomal Dominant Thyroid Hormone Resistance, (example, Chaves_2021). 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 (example, Yagi_1997). The most pronounced variant effect results in 16% of normal T3-dependent transactivation activity. This suggests that the receptor DNA-binding domain can modulate the function of the hormone-binding domain via allosteric mechanisms. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002476959 SCV002795863 pathogenic Selective pituitary resistance to thyroid hormone; Thyroid hormone resistance, generalized, autosomal dominant; Thyroid hormone resistance, generalized, autosomal recessive 2021-12-23 criteria provided, single submitter clinical testing
OMIM RCV000013394 SCV000033641 pathogenic Thyroid hormone resistance, generalized, autosomal dominant 1997-05-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000013394 SCV000692409 pathogenic Thyroid hormone resistance, generalized, autosomal dominant 2012-01-03 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004754259 SCV005362648 pathogenic THRB-related disorder 2024-05-01 no assertion criteria provided clinical testing The THRB c.728G>A variant is predicted to result in the amino acid substitution p.Arg243Gln. This variant has been reported in heterozygous patients with resistance to thyroid hormone (see, for example, Yagi et al. 1997. PubMed ID: 9141558; Lado Abeal et al. 2011. PubMed ID: 21703645; Macchia et al. 2014. PubMed ID: 25040256). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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