Submissions for variant NM_001354712.2(THRB):c.1378G>A (p.Glu460Lys)

dbSNP: rs1553609090

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800809	SCV002046468	likely pathogenic	not provided	2020-12-04	criteria provided, single submitter	clinical testing	The variant has been reported in affected individuals with thyroid hormone resistance in the published literature (PMIDs: 8040303 (1994), 20237409 (2010), 28938413 (2017), 30707410 (2019), and 30976996 (2019). A functional study showed lowered affinity for T3 binding by receptors (PMID: 8040303 (1994)). Based on the available information, the variant is predicted to be likely pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV002221242	SCV002498613	pathogenic	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta	2022-04-05	criteria provided, single submitter	clinical testing	This sequence change in THRB is predicted to replace glutamic acid with lysine at codon 460, p.(Glu460Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the nuclear hormone receptor ligand-binding domain. There is a small physicochemical difference between glutamic acid and lysine. This variant is absent from gnomAD v2.1 and v3.1. It has been reported in at least 8 probands diagnosed with resistance to thyroid hormone and segregate with disease in at least 6 families (PMID: 8040303, 10852467, 28938413, 32635414, 33768782). In vitro ligand-binding assays showed impaired T3-binding affinity indicating that this variant impacts protein function (PMID: 8040303, 10852467). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000583209	SCV004099761	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2023-09-12	criteria provided, single submitter	clinical testing	Variant summary: THRB c.1378G>A (p.Glu460Lys) 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 benign effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.1378G>A has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance (e.g. Adams_1994, Huang_2021, Xie_2022). 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, finding that the variant results in substantially reduced ligand binding activity of the receptor (Adams_1994). The following publications have been ascertained in the context of this evaluation (PMID: 8040303, 33768782, 35850606). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000583209	SCV005399565	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are reported mechanisms of disease in this gene and are associated with thyroid hormone resistance. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Autosomal dominant disease is due to the THRB mutant protein exerting a dominant negative effect on the wild type protein while recessive disease has been described in association with a THRB gene deletion where a protein is not produced (PMID: 30976996). (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability and heterogeneity are well documented in affected individuals (PMID: 30976996). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 35850606). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been regarded as pathogenic (ClinVar, PMID: 30976996) and detected in multiple individuals with elevated thyroid hormones (PMIDs: 33768782, 35850606, 32635414, 8040303, 30707410). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site directed mutagenesis followed by ligand-binding assays showed decreased T3-binding affinity compared to wild type (PMID: 8040303). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001800809	SCV005848236	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduction on T3 binding affinity (PMID: 8040303); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10852467, 28938413, 8040303, 20237409, 30976996, 32635414, 35850606, 30707410, 33768782, 36506769, 37592301)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583209	SCV000692437	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2012-06-15	no assertion criteria provided	clinical testing