Submissions for variant NM_001354712.2(THRB):c.727C>T (p.Arg243Trp)

gnomAD frequency: 0.00001  dbSNP: rs121918707

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657921	SCV000779688	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9141558, 9804773, 20237409, 26425626, 8664910, 33333891, 24174637, 26041374)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657921	SCV001470659	pathogenic	not provided	2020-09-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31406 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been identified among a cohort of subjects with resistance to thyroid hormone (RTH) and has shown syndrome cosegregation (PMIDs: 8664910 (1996), 20237409 (2010), 26425626 (2014)). Furthermore, it has been identified as de novo and functional studies have shown it causes decreased ligand binding activity compared to the wild-type in a dominant negative manner (PMIDs: 9707435 (1998), 9804773 (1998), 24174637 (2014)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000013395	SCV004813603	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: THRB c.727C>T (p.Arg243Trp) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) 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 250638 control chromosomes. c.727C>T has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (Pohlenz_1996, Glymph_2014, Pajek_2020) and observed to segregate with disease. 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 indicate a significant affect on protein function (Shi_2014, Safer_1998). The following publications have been ascertained in the context of this evaluation (PMID: 33333891, 8664910, 9804773, 24174637, 26425626).ClinVar contains an entry for this variant (Variation ID: 12567). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000013395	SCV000033642	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	1996-01-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000013395	SCV000692407	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2015-09-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904833	SCV004733988	pathogenic	THRB-related disorder	2024-01-23	no assertion criteria provided	clinical testing	The THRB c.727C>T variant is predicted to result in the amino acid substitution p.Arg243Trp. This variant has been reported in multiple unrelated individuals with thyroid hormone resistance (Pohlenz et al. 1996. PubMed ID: 8664910; Safer et al. 1998. PubMed ID: 9804773; Shi et al. 2014. PubMed ID: 24174637). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.