Submissions for variant NM_001354712.2(THRB):c.928A>G (p.Met310Val)

dbSNP: rs1553611094

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000581661	SCV005077445	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: THRB c.928A>G (p.Met310Val) 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 251438 control chromosomes (gnomAD). c.928A>G has been reported in the literature in multiple individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant (e.g. Amor_2014, Campi_2020, Moran_2021). Other missense changes affecting this amino acid have been determined to be pathogenic, suggesting this is a functionally important residue. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24722129, 32733382, 33524107). ClinVar contains an entry for this variant (Variation ID: 492914). Based on the evidence outlined above, the variant was classified as pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000581661	SCV005088731	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2021-07-22	criteria provided, single submitter	clinical testing	This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). It was previously reported in individuals with resistance to thyroid hormone (RTH) in heterozygous state [PMID: 20237409, 24722129]. In addition, other missense variants such as: p.Met310Thr and p.Met310Leu affecting the same codon of the identified variant have been reported as ‘pathogenic’ in the ClinVar database.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000356	SCV005625627	uncertain significance	not provided	2024-06-28	criteria provided, single submitter	clinical testing	The THRB c.928A>G (p.Met310Val) variant has been reported in the published literature in a family with resistance to thyroid hormone (RTH) (PMID: 24722129 (2014)). 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, we are unable to determine the clinical significance of this variant.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581661	SCV000692413	pathogenic	Thyroid hormone resistance, generalized, autosomal dominant	2014-05-06	no assertion criteria provided	clinical testing