Submissions for variant NM_001354712.2(THRB):c.803C>G (p.Ala268Gly)

dbSNP: rs750905761

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002222559	SCV002499798	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Not observed at a 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: 24393243, 19268523, 8956060, 30976996)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000583247	SCV004099762	likely pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2023-09-12	criteria provided, single submitter	clinical testing	Variant summary: THRB c.803C>G (p.Ala268Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251360 control chromosomes. c.803C>G has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (example, ElShafie_2014, Rivolta_2009). Particularly, this variant has been reported to co-segregate with disease in 11 affected cases and not present in the unaffected individuals of a large family diagnosed with autosomal dominant Thyroid Hormone Resistance, as a communication that has not provided enough clinical/genetic details (Jezequel_1996). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24393243, 8956060, 19268523). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003403374	SCV004119090	likely pathogenic	THRB-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	The THRB c.803C>G variant is predicted to result in the amino acid substitution p.Ala268Gly. This variant has been reported in multiple patients and families with thyroid resistance (Jézéquel et al. 1996. PubMed ID: 8956060; El Shafie et al. 2014. PubMed ID: 24393243; Rivolta et al. 2009. PubMed ID: 19268523). It has not been reported in a large population database (http://gnomad.broadinstitute.org/), indicating that it is rare. Taken together, we interpret this variant as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787999	SCV005398545	pathogenic	Thyroid hormone resistance syndrome	2021-05-06	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: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with thyroid hormone resistance (OMIM). 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant disease is due to the THRB mutant protein exerting a dominant negative effect on the wild type protein while recessive disease is due to a full deletion of a single THRB allele where a protein is not produced (PMID: 30976996). (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability and heterogeneity is well documented in affected individuals (PMID: 30976996). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Ala268Asp) variant has been identified in three individuals with resistance to thyroid hormone (PMIDs: 9707435, 27853072). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as heterozygous in four individuals with clinically confirmed resistance to thyroid hormone (PMIDs: 8956060, 19268523, 20237409, 24393243). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002222559	SCV005625625	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing	The THRB c.803C>G (p.Ala268Gly) variant has been reported in the published literature in individuals/families with clinical features of resistance to thyroid hormone (RTH) syndrome (PMID: 24393243 (2014), 19268523 (2009), 8956060 (1996)), and is observed to be statistically associated with disease in one family (PMID: 8956060 (1996)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583247	SCV000692411	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2012-02-21	no assertion criteria provided	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000761462	SCV000891559	likely pathogenic	Thyroid hormone resistance, generalized, autosomal recessive	2017-12-30	no assertion criteria provided	curation