Submissions for variant NM_000369.5(TSHR):c.1349G>A (p.Arg450His)

gnomAD frequency: 0.00023  dbSNP: rs189261858

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490528	SCV000267546	pathogenic	Hypothyroidism due to TSH receptor mutations	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000273881	SCV000329921	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Published functional studies of transfected COS-7 cells showed slightly decreased cAMP production and a slightly decreased binding to thyroid stimulating hormone (Nagashima et al., 2001); 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: 22405933, 30083029, 28444304, 21677043, 29650690, 22876533, 21714469, 11442002, 15693879, 19158199, 27637299, 27084275, 29092890, 26990548, 28455095, 30022773, 31356790, 21707688, 29973617, 30577886, 32425884, 34248839, 23926367, 31589614, 32319661, 32459320)
Illumina Laboratory Services, Illumina	RCV000490528	SCV000915656	pathogenic	Hypothyroidism due to TSH receptor mutations	2018-08-15	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the TSHR c.1349G>A (p.Arg450His) missense variant has been identified in a homozygous state in at least ten individuals with congenital hypothyroidism, in a compound heterozygous state in at least four patients, and in a heterozygous state in ten patients in whom a second variant was not identified (Shibayama et al. 2005; Mizuno et al. 2009; Lee et al. 2011; Narumi et al. 2011; Chang et al. 2012; Fu et al. 2016). In at least one family, unaffected parents were identified as heterozygous carriers of the p.Arg450His variant. This variant was absent from 300 control chromosomes, but is reported at a frequency of 0.00335 in the East Asian population from the Exome Aggregation Consortium. In COS-7 cells, the p.Arg450His variant demonstrated slightly decreased cAMP production and slightly decreased TSH binding compared to wild type (Nagashima et al. 2001). In HEK293 cells, the p.Arg450His variant demonstrated 42% activity for Gs-coupled signaling and 8% activity for Gq-coupled signaling compared to wildtype (Narumi et al. 2011). Based on the collective evidence, the p.Arg450His 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826152	SCV000967686	pathogenic	Congenital hypothyroidism	2018-07-17	criteria provided, single submitter	clinical testing	The p.Arg450His variant in TSHR has been reported in the homozygous or compound heterozygous state in >20 individuals with congenital hypothyroidism (Nagashima 2001, Shibayama 2005, Kanda 2006, Narumi 2009, Mizuno 2009, Satoh 2009, Ma 2010, Lee 2011, Narumi 2011, Chang 2012, Tsunekawa 2014, Park 2016, Wang 2017). Heter ozygous family members frequently displayed subclinical hypothyroidism (Ma 2010, Narumi 2009, Kanda 2006, Nagashima 2001). A significant association between the p.Arg450His variant and the risk of congenital hypothyroidism has been observed in one study (Chang 2012). This variant has been identified in 0.26% (49/18868) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs189261858). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. In vitro functional studies provide some evidence that the p.Arg450H is variant may impact protein function (Nagashima 2001, Narumi 2009, Narumi 2011 ); however, these types of assays may not accurately represent biological functi on. Computational prediction tools and conservation analysis suggest that the p. Arg450His variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, this variant meets our criter ia to be classified as pathogenic for congenital hypothyroidism in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PP3; PS3_Supporting .
CeGaT Center for Human Genetics Tuebingen	RCV000273881	SCV001961453	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000273881	SCV003442345	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the TSHR protein (p.Arg450His). This variant is present in population databases (rs189261858, gnomAD 0.3%). This missense change has been observed in individual(s) with autosomal recessive congenital hypothyroidism (PMID: 11442002, 19506388, 21677043, 30083029, 31356790). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TSHR function (PMID: 11442002, 16756469, 21677043, 30083029). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225722	SCV003807742	pathogenic	Familial gestational hyperthyroidism	2022-09-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153491	SCV003843675	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000490528	SCV004175669	pathogenic	Hypothyroidism due to TSH receptor mutations	2021-12-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000273881	SCV004238775	likely pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing