chr14-81143695-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000369.5(TSHR):c.1637G>A(p.Trp546*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,084 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_000369.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSHR | NM_000369.5 | c.1637G>A | p.Trp546* | stop_gained | Exon 10 of 10 | ENST00000298171.7 | NP_000360.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSHR | ENST00000298171.7 | c.1637G>A | p.Trp546* | stop_gained | Exon 10 of 10 | 1 | NM_000369.5 | ENSP00000298171.2 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251346Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135838
GnomAD4 exome AF: 0.000289 AC: 423AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.000290 AC XY: 211AN XY: 727240
GnomAD4 genome AF: 0.000191 AC: 29AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74362
ClinVar
Submissions by phenotype
not provided Pathogenic:4
DNA sequence analysis of the TSHR gene demonstrated a sequence change, c.1637G>A in exon 10, which results in the creation of a premature stop codon at amino acid position 546, p.Trp546*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHR protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous state in patients with congenital hypothyroidism (PMIDs: 12629076, 14725684). Functional studies have also demonstrated reduced expression of receptors on the cell surface and decreased binding affinity in cells transiently transfected with the p.Trp546* sequence change (PMID: 9100579). -
This sequence change creates a premature translational stop signal (p.Trp546*) in the TSHR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acid(s) of the TSHR protein. This variant is present in population databases (rs121908866, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with thyroid-stimulating hormone (TSH) resistance and autosomal recessive congenital hypothyroidism (PMID: 8954020, 9100579, 12629076, 14725684). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6439). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHR function (PMID: 9100579). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate that this variant results in a nonfunctional protein, with negligible membrane radioligand binding (PMID: 9100579); Nonsense variant predicted to result in protein truncation, as the last 219 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 14725684, 15863666, 12629076, 27637299, 30665703, 34308104, 29625052, 34200080, 34662886, 35177841, 36451132, 8954020, 9100579) -
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Hypothyroidism due to TSH receptor mutations Pathogenic:3
Variant summary: TSHR c.1637G>A (p.Trp546X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 251346 control chromosomes. c.1637G>A has been reported in the literature in multiple individuals affected with Hypothyroidism Due To TSH Receptor Mutations (e.g. Jordan_2003, deRoux_1996, Clifton_Bligh_1997). 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 indicating reduced surface receptor expression and negligible binding activity(Clifton_Bligh_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9100579, 12629076, 8954020). ClinVar contains an entry for this variant (Variation ID: 6439). Based on the evidence outlined above, the variant was classified as pathogenic. -
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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. -
Inborn genetic diseases Pathogenic:1
The c.1637G>A (p.W546*) alteration, located in exon 10 (coding exon 10) of the TSHR gene, consists of a G to A substitution at nucleotide position 1637. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 546. Although biallelic loss of function alterations in TSHR have been associated with congenital nongoitrous hypothyroidism, haploinsufficiency for TSHR has not been established as a mechanism of disease for nonautoimmune hyperthyroidism. Based on the available evidence, the TSHR c.1637G>A (p.W546*) alteration is classified as pathogenic for autosomal recessive congenital nongoitrous hypothyroidism; however, it is unlikely to be causative of autosomal dominant nonautoimmune hyperthyroidism. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (31/282748) total alleles studied. The highest observed frequency was 0.02% (28/129080) of European (non-Finnish) alleles. This alteration has been detected in both homozygous and compound heterozygous states in individuals with autosomal recessive congenital hypothyroidism (Biebermann, 2012; Clifton-Bligh, 1997; Jordan, 2003; Park, 2004). Functional studies showed that cells transiently transfected with this mutation have nonfunctional TSH receptor with negligible membrane radioligand binding (Clifton-Bligh, 1997). Based on the available evidence, this alteration is classified as pathogenic. -
TSHR-related disorder Pathogenic:1
The TSHR c.1637G>A variant is predicted to result in premature protein termination (p.Trp546*). This variant has been reported in the homozygous and compound heterozygous states in individuals with congenital hypothyroidism and thyroid hormone resistance (Clifton-Bligh et al. 1997. PubMed ID: 9100579; Jordan et al. 2003. PubMed ID: 12629076; Park et al. 2004. PubMed ID: 14725684). A heterozygous carrier in one study was also found to have abnormal thyroid function (Park et al. 2004. PubMed ID: 14725684). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-81610039-G-A). Nonsense variants in TSHR are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Familial hyperthyroidism due to mutations in TSH receptor;C1863959:Familial gestational hyperthyroidism;C3493776:Hypothyroidism due to TSH receptor mutations Pathogenic:1
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Computational scores
Source:
Splicing
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