ClinVar Miner

Submissions for variant NM_000369.2(TSHR):c.1637G>A (p.Trp546Ter) (rs121908866)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000333686 SCV000329922 pathogenic not provided 2018-10-07 criteria provided, single submitter clinical testing The W546X variant in the TSHR gene has been reported previously in association with congenital hypothyroidism or resistance to TSH (RTSH) when present in the homozygous state or compound heterozygous state with another TSHR variant; parents who were determined to be heterozygous for this variant demonstrated normal thyroid function (de Roux et al., 1996; Clifton-Bligh et al., 1997; Jordan et al., 2003). The W546X variant is predicted to cause loss of normal protein function through protein truncation. Functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (Clifton-Bligh et al., 1997). The W546X variant is observed in 25/126,582 alleles (0.02%) from individuals of non-Finnish European background and 28/277,066 total alleles (0.01%) in large population cohorts (Lek et al., 2016). We interpret W546X as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000292905 SCV000389148 benign Hyperthyroidism, nonautoimmune 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000006809 SCV000389149 pathogenic Hypothyroidism, congenital, nongoitrous, 1 2017-04-27 criteria provided, single submitter clinical testing The TSHR c.1637G>A (p.Trp546Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp546Ter variant has been reported in at least four studies in which it is found in a total of six patients with congenital hypothyroidism including in two in a homozygous state and in four in a compound heterozygous state, all with a second missense variant (de Roux et al. 1996; Clifton-Bligh et al. 1997; Jordan et al. 2003; Park et al. 2004). The p.Trp546Ter variant was found in two of 368 controls and is reported at a frequency of 0.00058 in the European-American population of the Exome Sequencing Project. Functional studies in COS-7 and JEG3 cells demonstrated reduced expression of receptors on the cell surface and decreased binding affinity in cells transiently transfected with the p.Trp546Ter variant (de Roux et al. 1996; Clifton-Bligh et al. 1997). Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp546Ter variant is classified as pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000006809 SCV000027005 pathogenic Hypothyroidism, congenital, nongoitrous, 1 2003-03-01 no assertion criteria provided literature only

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