Submissions for variant NM_000549.5(TSHB):c.205C>T (p.Gln69Ter)

gnomAD frequency: 0.00002  dbSNP: rs121918670

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000013524	SCV000914343	likely pathogenic	Isolated thyroid-stimulating hormone deficiency	2019-01-12	criteria provided, single submitter	clinical testing	The TSHB c.205C>T (p.Gln69Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln69Ter variant is described in two studies in which it is detected in a homozygous state in three individuals from two families with congenital hypothyroidism, two of whom are related (Bonomi et al. 2001; Vuissoz et al. 2001). The variant was also detected in a heterozygous state in both sets of parents and three unaffected siblings. Control data are unavailable for the p.Gln69Ter variant which is reported at a frequency of 0.000039 in the European (non-Finnish) population of the Genome Aggregation Database. Serum-TSH was extremely low in the affected homozygotes and stimulation with TRH failed to induce a TSH release. The p.Gln69Ter variant is predicted to result in a peptide lacking at least 50% of the C-terminal region of the protein. The truncated peptide does not contain the seat belt region of the protein, a region critical for the dimerization with the alpha-subunit and hence for the correct secretion of the mature TSH heterodimer. Based on the evidence, the p.Gln69Ter 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.
3billion	RCV000013524	SCV002520987	pathogenic	Isolated thyroid-stimulating hormone deficiency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:11549695). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000012687 / PMID: 11297590). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000013524	SCV003823746	pathogenic	Isolated thyroid-stimulating hormone deficiency	2021-12-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415693	SCV004107170	pathogenic	TSHB-related condition	2023-04-28	criteria provided, single submitter	clinical testing	The TSHB c.205C>T variant is predicted to result in premature protein termination (p.Gln69*). This variant has been reported in the homozygous and compound heterozygous states in individuals with hypothyroidism (Bonomi et al. 2001. PubMed ID: 11297590; reported as Q49X in Karges et al. 2004. PubMed ID: 15297803). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115576636-C-T). Nonsense variants in TSHB are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12687/). Given the evidence, we interpret this variant as pathogenic.
Invitae	RCV003556008	SCV004291975	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln69*) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the TSHB protein. This variant is present in population databases (rs121918670, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital hypothyroidism (PMID: 11297590, 11549695, 15297803). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q49X. ClinVar contains an entry for this variant (Variation ID: 12687). This variant disrupts a region of the TSHB protein in which other variant(s) (p.Cys125Valfs*10) have been determined to be pathogenic (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013524	SCV000033771	pathogenic	Isolated thyroid-stimulating hormone deficiency	2001-09-01	no assertion criteria provided	literature only