rs121912648
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_003235.5(TG):c.886C>T(p.Arg296Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,614,008 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00055 ( 3 hom. )
Consequence
TG
NM_003235.5 stop_gained
NM_003235.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.54
Genes affected
TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 8-132882609-C-T is Pathogenic according to our data. Variant chr8-132882609-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132882609-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TG | NM_003235.5 | c.886C>T | p.Arg296Ter | stop_gained | 7/48 | ENST00000220616.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TG | ENST00000220616.9 | c.886C>T | p.Arg296Ter | stop_gained | 7/48 | 1 | NM_003235.5 | P1 | |
| TG | ENST00000520769.1 | n.239C>T | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes 0.000394 AC: 60AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000362 AC: 91AN: 251480Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135916
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GnomAD4 exome AF: 0.000549 AC: 803AN: 1461888Hom.: 3 Cov.: 31 AF XY: 0.000528 AC XY: 384AN XY: 727246
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GnomAD4 genome 0.000394 AC: 60AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30AN XY: 74310
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Iodotyrosyl coupling defect Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 24, 2018 | The TG c.886C>T (p.Arg296Ter) variant is a stop-gained variant which has been reported in at least six studies in which it is found in a total of 15 patients with clinical suspicion of thyroid dyshoromonogenesis, including five in a homozygous state and ten in a compound heterozygous state (van de Graaf et al. 1999; Gutnisky et al. 2004; Rivolta et al. 2005; Peteiro-Gonzalez et al. 2010; Citterio et al. 2011; Citterio et al. 2013). In all families, the p.Arg296Ter variant was identified in unaffected individuals in a heterozygous state. Control data are unavailable for this variant, which is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. RT-PCR analysis on patient cDNA showed very little transcript was present from the p.Arg296Ter variant allele (Peteiro-Gonzalez et al. 2010). Based on the collective evidence, the p.Arg296Ter variant is classified as pathogenic for thyroid dyshormonogenesis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 17, 2014 | This patient is a carrier of a heterozygous pathogenic variant in the TG gene associated with thyroid dyshormonogenesis. The TG variant (c.886C>T; p.Arg296*) identified in this patient is a nonsense variant which results in a truncated protein, considered a pathogenic variant and has been reported in other individuals with goitre and hypothyroidism (Van da Graaf et al. 1999, PMID: 10404833; Gutnisky et al. 2004, PMID: 14764776; Rivolta et al. 2005, PMID: 15769978; Caputo et al. 2007, PMID: 17532758; Peteiro-Gonzalez et al. 2010, PMID: 20410234). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 20, 2020 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg296*) in the TG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TG are known to be pathogenic (PMID: 19837936, 23164529). This variant is present in population databases (rs121912648, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with congenital hypothyroidism and goiter (PMID: 10404833, 14764776, 20410234, 21372558, 23164529). It has also been observed to segregate with disease in related individuals. This variant is also known as R277X. ClinVar contains an entry for this variant (Variation ID: 12695). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 09, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23164529, 21128992, 25525159, 20410234, 9588493, 15769978, 26990548, 28359061, 29546359, 29275168, 28176629, 34426522, 33692749, 32765423, 31589614, 33321114, 10404833, 14764776) - |
TG-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2024 | The TG c.886C>T variant is predicted to result in premature protein termination (p.Arg296*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with goiter and hypothyroidism (van de Graaf et al. 1999. PubMed ID: 10404833; Peteiro-Gonzalez et al. 2010. PubMed ID: 20410234; Siffo et al. 2017. PubMed ID: 29275168; Zou et al. 2018. PubMed ID: 29546359). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in TG are expected to be pathogenic. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | Variant summary: TG c.886C>T (p.Arg296X) results in a premature termination codon, predicted to cause nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00036 in 251480 control chromosomes. c.886C>T has been reported in the literature in multiple individuals affected with TG-Related Disorders (example, van de Graaf_1999). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (van de Graaf_1999). The following publication have been ascertained in the context of this evaluation (PMID: 10404833). ClinVar contains an entry for this variant (Variation ID: 12695). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Congenital hypothyroidism Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Polak associated Lab, IMAGINE Institute | - | - - |
Iodotyrosyl coupling defect;C1842444:Autoimmune thyroid disease, susceptibility to, 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at