VCV000012695.24 - ClinVar

NM_003235.5(TG):c.886C>T (p.Arg296Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003235.5(TG):c.886C>T (p.Arg296Ter)

Variation ID: 12695 Accession: VCV000012695.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.22 8: 132882609 (GRCh38) [ NCBI UCSC ] 8: 133894854 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 5, 2015	Jan 25, 2025	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003235.5:c.886C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003226.4:p.Arg296Ter	nonsense
NC_000008.11:g.132882609C>T
NC_000008.10:g.133894854C>T
NG_015832.1:g.20650C>T

Protein change

R296*

Other names

R277*

Canonical SPDI

NC_000008.11:132882608:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00036

The Genome Aggregation Database (gnomAD), exomes 0.00036

The Genome Aggregation Database (gnomAD) 0.00041

Trans-Omics for Precision Medicine (TOPMed) 0.00045

Links

ClinGen: CA210703 OMIM: 188450.0007 dbSNP: rs121912648 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TG		-	-	GRCh38 GRCh37	1873	2047

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Iodotyrosyl coupling defect	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 20, 2020	RCV000013532.30
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 16, 2024	RCV000299644.12
Congenital hypothyroidism	Pathogenic (1)	no assertion criteria provided	-	RCV001270319.1
Autoimmune thyroid disease, susceptibility to, 3 Iodotyrosyl coupling defect	Pathogenic (1)	criteria provided, single submitter	Jun 7, 2024	RCV002496346.2
TG-related disorder	Pathogenic (2)	criteria provided, single submitter	Apr 15, 2024	RCV004586002.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 09, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332807.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TG Number of individuals with the variant: 3 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Jan 24, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Iodotyrosyl coupling defect Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000471993.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (6) PubMed: 14764776‚ 10404833‚ 23164529‚ 20410234‚ 21128992‚ 15769978 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Iodotyrosyl coupling defect Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018958.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003254003.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 19837936‚ 23164529‚ 10404833‚ 14764776‚ 20410234‚ 21372558 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Iodotyrosyl coupling defect Autoimmune thyroid disease, susceptibility to, 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV002813089.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025
Pathogenic (Jul 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329973.10 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Apr 15, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	TG-Related Disorders Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005076184.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (1) PubMed: 10404833 Comment: 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. … (more) 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. (less)
Pathogenic (Jul 17, 2014)	no assertion criteria provided Method: research	Thyroid dysmorphogenesis 3, autosomal recessive (MIM 274700) Affected status: no Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000238411.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Publications: PubMed (1) PubMed: 20410234 Comment: 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 … (more) 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). (less)
Pathogenic (Jun 01, 2005)	no assertion criteria provided Method: literature only	THYROID DYSHORMONOGENESIS 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033779.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016	Publications: PubMed (4) PubMed: 10404833‚ 14764776‚ 9588493‚ 15769978 Comment on evidence: Van de Graaf et al. (1999) studied the TG mRNA from thyroid tissue of a 13-year-old patient with goiter and hypothyroidism who was suspected to … (more) Van de Graaf et al. (1999) studied the TG mRNA from thyroid tissue of a 13-year-old patient with goiter and hypothyroidism who was suspected to have a TG synthesis defect (TDH3; 274700). The complete coding region was directly sequenced, revealing a homozygous C-to-T transition at nucleotide 886 in exon 7, resulting in an arg277-to-ter mutation (R277X). Two other sibs presented with the same clinical findings as the index patient, but their parents were unaffected. Additional RFLP analysis of the pedigree verified that the homozygous nonsense mutation cosegregated with the clinical phenotype. Clinically, hypothyroidism was not severe in the affected sibs, because the truncated TG glycoprotein was still capable of thyroid hormonogenesis. Gutnisky et al. (2004) found this mutation in the Brazilian family originally reported by Targovnik et al. (1989). Affected members of this family carried the R277X mutation in compound heterozygous state with either R1511X (188450.0003) or a splice site mutation (188450.0013). Gutnisky et al. (2004) presented evidence that a founder effect accounts for the R277X mutation in their family and that reported by Van de Graaf et al. (1999). Rivolta et al. (2005) reported this mutation in an Argentinian patient with congenital goiter, hypothyroidism, and impairment of TG synthesis. Haplotype analysis in this patient and one previously reported with the mutation suggested that a mutational hotspot at nucleotide 886, rather than founder effect, accounts for the recurrence of the mutation. (less)
Pathogenic (Aug 07, 2024)	no assertion criteria provided Method: clinical testing	TG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345436.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Congenital hypothyroidism Affected status: yes Allele origin: germline	Polak associated Lab, IMAGINE Institute Accession: SCV001450542.1 First in ClinVar: Dec 16, 2020 Last updated: Dec 16, 2020	Publications: PubMed (1) PubMed: 10404833
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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).

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism.	Citterio CE	Molecular and cellular endocrinology	2013	PMID: 23164529
Thyroglobulin gene mutations in congenital hypothyroidism.	Targovnik HM	Hormone research in paediatrics	2011	PMID: 21372558
A new compound heterozygous for c.886C>T/c.2206C>T [p.R277X/p.Q717X] mutations in the thyroglobulin gene as a cause of foetal goitrous hypothyroidism.	Citterio CE	Clinical endocrinology	2011	PMID: 21128992
New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.	Peteiro-Gonzalez D	The Journal of clinical endocrinology and metabolism	2010	PMID: 20410234
Six new mutations of the thyroglobulin gene discovered in taiwanese children presenting with thyroid dyshormonogenesis.	Niu DM	The Journal of clinical endocrinology and metabolism	2009	PMID: 19837936
A new case of congenital goiter with hypothyroidism caused by a homozygous p.R277X mutation in the exon 7 of the thyroglobulin gene: a mutational hot spot could explain the recurrence of this mutation.	Rivolta CM	The Journal of clinical endocrinology and metabolism	2005	PMID: 15769978
Two distinct compound heterozygous constellations (R277X/IVS34-1G>C and R277X/R1511X) in the thyroglobulin (TG) gene in affected individuals of a Brazilian kindred with congenital goiter and defective TG synthesis.	Gutnisky VJ	The Journal of clinical endocrinology and metabolism	2004	PMID: 14764776
A premature stopcodon in thyroglobulin messenger RNA results in familial goiter and moderate hypothyroidism.	van de Graaf SA	The Journal of clinical endocrinology and metabolism	1999	PMID: 10404833
Evidence for the segregation of three different mutated alleles of the thyroglobulin gene in a Brazilian family with congenital goiter and hypothyroidism.	Targovnik HM	Thyroid : official journal of the American Thyroid Association	1998	PMID: 9588493
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TG	-	-	-	-

Text-mined citations for rs121912648 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_003235.5(TG):c.886C>T (p.Arg296Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912648 ...