Submissions for variant NM_001354712.2(THRB):c.994G>A (p.Gly332Arg)

dbSNP: rs28999969

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000424820	SCV000511108	likely pathogenic	not provided	2016-07-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000424820	SCV001134861	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000424820	SCV001986265	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Also denoted as p.G327R due to alternative nomenclature; Identified in a patient with thyroid hormone resistance in the published literature (Parrilla et al., 1991); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8013151, 1661299, 20050372, 21871106)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265554	SCV002548028	uncertain significance	not specified	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: THRB c.994G>A (p.Gly332Arg) 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 251476 control chromosomes. c.994G>A has been reported in the literature in individuals affected with Autosomal Dominant Generalized Thyroid Hormone Resistance (example, Parrilla_1991 cited in Adams_1994, Macchia_2014, Alberobello_2011). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013370	SCV005399712	uncertain significance	Thyroid hormone resistance, generalized, autosomal dominant	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with thyroid hormone resistance (MIM#188570), thyroid hormone resistance, autosomal recessive (MIM#274300), and thyroid hormone resistance, selective pituitary (MIM#145650) (OMIM; PMID: 30976996). (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 glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Gly332Glu) has been reported in two individuals with thyroid hormone resistance (PMID: 8040303, 34556608). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been submitted to ClinVar three times as VUS and once as likely pathogenic by clinical laboratories. Additionally, it has been reported in a single individual with generalised thyroid hormone resistance, language difficulties, and below average IQ (PMID: 1661299, 25040256). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000013370	SCV000033617	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	1994-05-01	no assertion criteria provided	literature only