ClinVar Miner

Submissions for variant NM_000369.2(TSHR):c.394G>C (p.Gly132Arg) (rs760874290)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Illumina Clinical Services Laboratory,Illumina RCV000400375 SCV000389130 uncertain significance Hypothyroidism, congenital, nongoitrous, 1 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 Clinical Services Laboratory,Illumina RCV000308671 SCV000389131 benign Hyperthyroidism, nonautoimmune 2016-06-14 criteria provided, single submitter clinical testing

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