Submissions for variant NM_000369.5(TSHR):c.1657G>A (p.Ala553Thr)

dbSNP: rs121908872

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000006815	SCV000389150	likely pathogenic	Hypothyroidism due to TSH receptor mutations	2017-04-27	criteria provided, single submitter	clinical testing	The TSHR c.1657G>A (p.Ala553Thr) missense variant is described in five studies in which it is identified in seven patients with congenital hyopthyroidism including in a homozygous state in two pairs of consanguineous siblings and in a compound heterozygous state in two non-consanguineous siblings and an additional unrelated patient (Abramowicz et al. 1997; Park et al. 2004; Cangul et al. 2010; Cangul et al. 2012; van Tellingen et al. 2016). The variant was absent from 400 control alleles but is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Functional studies in COS-7 cells demonstrated that the p.Ala553Thr variant resulted in extremely low cell-surface expression of the receptor compared to wild type (Abramowicz et al. 1997). The Ala553 residue is highly conserved (Abramowicz et al. 1997; Cangul et al. 2010). Stability studies showed that the variant was expected to be significantly destabilizing for the protein (Cangul et al. 2010). Based on the collective evidence, the p.Ala553Thr variant is classified as likely pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago	RCV000006815	SCV000597611	likely pathogenic	Hypothyroidism due to TSH receptor mutations	2016-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512853	SCV003737894	pathogenic	Inborn genetic diseases	2021-09-08	criteria provided, single submitter	clinical testing	The c.1657G>A (p.A553T) alteration is located in exon 10 (coding exon 10) of the TSHR gene. This alteration results from a G to A substitution at nucleotide position 1657, causing the alanine (A) at amino acid position 553 to be replaced by a threonine (T). Based on the available evidence, this variant is expected to be causative of congenital nongoitrous hypothyroidism (AR) when present along with a second pathogenic or likely pathogenic variant on the other allele; however, it is unlikely to be causative of nonautoimmune hyperthyroidism (AD). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (8/251360) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This alteration has been detected in the homozygous state or compound heterozygous with a second TSHR variant in multiple unrelated individuals with congenital hypothyroidism (Abramowicz, 1997; Park, 2004; Cangul, 2010; van Tellingen, 2016). Heterozygous carriers of this variant have been reported with subclinical or mild hypothyroidism (Nicoletti, 2009; Abe, 2018). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764533	SCV004678595	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the TSHR protein (p.Ala553Thr). This variant is present in population databases (rs121908872, gnomAD 0.006%). This missense change has been observed in individual(s) with hypothyroidism (PMID: 9185526, 14725684, 20718767, 27255745, 29092890). 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: 6445). 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: 9185526, 10560953). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004566686	SCV005054531	pathogenic	Familial gestational hyperthyroidism	2024-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006815	SCV005185716	pathogenic	Hypothyroidism due to TSH receptor mutations	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: TSHR c.1657G>A (p.Ala553Thr) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251360 control chromosomes. c.1657G>A has been reported in the literature in multiple biallelic individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Abramowicz_1997, Cangul_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced TSH-induced cyclic adenosine monophosphate (cAMP) signaling in COS-7 cells (Abramowicz_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9185526, 20718767). ClinVar contains an entry for this variant (Variation ID: 6445). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005007831	SCV005635617	pathogenic	Familial gestational hyperthyroidism; Familial hyperthyroidism due to mutations in TSH receptor; Hypothyroidism due to TSH receptor mutations	2024-05-16	criteria provided, single submitter	clinical testing
OMIM	RCV000006815	SCV000027011	pathogenic	Hypothyroidism due to TSH receptor mutations	1997-06-15	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532302	SCV004745657	likely pathogenic	TSHR-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The TSHR c.1657G>A variant is predicted to result in the amino acid substitution p.Ala553Thr. This variant has been reported in the monoallelic or bi-allelic state in individuals with Hypothyroidism (Abramowicz et al. 1997. PubMed ID: 9185526; Park et al. 2004. PubMed ID: 14725684; Abe et al. 2017. PubMed ID: 29092890). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.