rs121912648

Variant names:

• chr8-132882609-C-T
• rs121912648
• NM_003235.5:c.886C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003235.5(TG):​c.886C>T​(p.Arg296*) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
TG	NM_003235.5	c.886C>T	p.Arg296*	stop_gained	Exon 7 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.886C>T	p.Arg296*	stop_gained	Exon 7 of 48	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000520769.1	n.239C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251480 Hom.: 0 AF XY: 0.000361 AC XY: 49 AN XY: 135916

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000549 AC: 803 AN: 1461888 Hom.: 3 Cov.: 31 AF XY: 0.000528 AC XY: 384 AN XY: 727246

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000629

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74310

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000526 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Iodotyrosyl coupling defect Pathogenic:4

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 20, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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). -

Jan 24, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 23, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 34200080, 25525159, 20410234, 9588493, 15769978, 26990548, 28359061, 29546359, 29275168, 28176629, 34426522, 33692749, 32765423, 31589614, 33321114, 31345219, 34780050, 35177841, 14764776, 10404833, 35649421, 34493867, 31430255, 36884306) -

TG-related disorder Pathogenic:2

Aug 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Apr 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Polak associated Lab, IMAGINE Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Iodotyrosyl coupling defect;C1842444:Autoimmune thyroid disease, susceptibility to, 3 Pathogenic:1

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.95
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912648; hg19: chr8-133894854;