chr1-115034015-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000549.5(TSHB):c.205C>T(p.Gln69*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000273 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000549.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251322Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135824
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461488Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727052
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
Isolated thyroid-stimulating hormone deficiency Pathogenic:4
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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. -
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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. -
TSHB-related disorder Pathogenic:1
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. -
not provided Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at