Submissions for variant NM_000369.5(TSHR):c.394G>C (p.Gly132Arg)

gnomAD frequency: 0.00004  dbSNP: rs760874290

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000400375	SCV000389130	uncertain significance	Hypothyroidism due to TSH receptor mutations	2017-04-28	criteria provided, single submitter	clinical testing	The TSHR c.394G>C (p.Gly132Arg) missense variant has been reported in at least three studies in which it is found in a total of six patients with congenital hypothyroidism, including in one in a homozygous state, in two in a compound heterozygous state, in two in a heterozygous state, and in a heterozygous state in one patient who also carried a missense variant in another congenital hypothyroidism-associated gene (Narumi et al. 2009; Lee et al. 2011; Jin et al. 2014). The majority of these studies, however, did not screen for all the known causal genes. The p.Gly132Arg variant was absent from 100 controls, but is reported at a frequency of 0.00047 in the East Asian population of the Exome Aggregation Consortium. Functional studies in COS-7 cells showed that the p.Gly132Arg variant protein was expressed at a level comparable to that of the wild type protein but displayed severely reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) (Narumi et al. 2009). The evidence for this variant is limited. The p.Gly132Arg variant is therefore classified as likley pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV000308671	SCV000389131	benign	Familial hyperthyroidism due to mutations in TSH receptor	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000489665	SCV000577623	likely pathogenic	not provided	2016-01-13	criteria provided, single submitter	clinical testing	The G132R variant in the TSHR gene has been reported previously in association with congenital hypothyroidism (Lee et al., 2011; Narumi et al., 2011). And, functional characterization of the G132R variant indicates a disruption in receptor function (Narumi et al., 2009). The G132R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant. The G132R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The G132R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153557	SCV003843358	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335304	SCV004046352	likely pathogenic	TSHR-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo compound heterozygous and homozygous change in patients with congenital nongoitrous hypothyroidism-1 (CHNG1) who exhibited increased levels of plasma TSH and low levels of thyroid hormone in infancy (PMID: 21707688, 19158199). Functional studies showed that the presence of the (p.Gly132Arg) variant resulted in reduced binding activity and impaired TSH-induced cAMP production (26% of wild type) without any significant reduction in expression level (PMID: 19158199). The c.394G>C (p.Gly132Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/280224) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.394G>C (p.Gly132Arg) variant is classified as Likely Pathogenic.
Baylor Genetics	RCV004567857	SCV005054530	likely pathogenic	Familial gestational hyperthyroidism	2024-03-26	criteria provided, single submitter	clinical testing