NM_003235.5(TG):c.229G>A (p.Gly77Ser) AND Iodotyrosyl coupling defect

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Dec 18, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000760170.13

Allele description [Variation Report for NM_003235.5(TG):c.229G>A (p.Gly77Ser)]

NM_003235.5(TG):c.229G>A (p.Gly77Ser)

Gene:

TG:thyroglobulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.22

Genomic location:

Preferred name:

NM_003235.5(TG):c.229G>A (p.Gly77Ser)

HGVS:

NC_000008.11:g.132869781G>A
NG_015832.1:g.7822G>A
NM_003235.5:c.229G>AMANE SELECT
NP_003226.4:p.Gly77Ser
NC_000008.10:g.133882026G>A
NM_003235.4:c.229G>A
p.Gly77Ser

Protein change:

G77S

Links:

dbSNP: rs142698837

NCBI 1000 Genomes Browser:

rs142698837

Molecular consequence:

NM_003235.5:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Iodotyrosyl coupling defect (TDH3)
Synonyms:: HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 3; THYROID HORMONOGENESIS, GENETIC DEFECT IN, 3
Identifiers:: MONDO: MONDO:0010135; MedGen: C0342194; Orphanet: 95716; OMIM: 274700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000889989	Center for Precision Medicine, Vanderbilt University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2018)	germline	research, in vitro	PubMed (3) [See all records that cite these PMIDs] 25741868, 19339519, 29590070
SCV001324740	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003819450	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175302	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10403171, 34484748, 25741868
SCV005685136	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	69	not provided	not provided	not provided	not provided	clinical testing, research, in vitro
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Human Splicing Finder: an online bioinformatics tool to predict splicing signals.

Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C.

Nucleic Acids Res. 2009 May;37(9):e67. doi: 10.1093/nar/gkp215. Epub 2009 Apr 1.

PubMed [citation]

PMID:: 19339519
PMCID:: PMC2685110

Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.

Bastarache L, Hughey JJ, Hebbring S, Marlo J, Zhao W, Ho WT, Van Driest SL, McGregor TL, Mosley JD, Wells QS, Temple M, Ramirez AH, Carroll R, Osterman T, Edwards T, Ruderfer D, Velez Edwards DR, Hamid R, Cogan J, Glazer A, Wei WQ, Feng Q, et al.

Science. 2018 Mar 16;359(6381):1233-1239. doi: 10.1126/science.aal4043.

PubMed [citation]

PMID:: 29590070
PMCID:: PMC5959723

See all PubMed Citations (5)

Details of each submission

From Center for Precision Medicine, Vanderbilt University Medical Center, SCV000889989.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	69	not provided	not provided	research	PubMed (3)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	discovery		69	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	discovery		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001324740.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003819450.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175302.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The TG c.229G>A variant is classified as Likely Pathogenic (PM1, PM3_Strong, PP3) The TG c.229G>A variant is a single nucleotide change in exon 3/48 of the TG gene, which is predicted to change the amino acid glycine at position 77 in the protein to serine. This variant is located in the conserved thyroglobulin-1 domain (PM1). This variant has been detected in trans with a pathogenic variant as well as homozygous in patients with congenital hypothyroidism (PMID:10403171, 34484748) (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs142698837), in population databases (gnomAD 104/152184, 0 homozygotes) and as disease causing in the HGMD database (CM994510). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 436996).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV005685136.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The TG c.229G>A (p.Gly77Ser) variant has been reported in at least eight individuals affected with goiter and/or moderate hypothyroidism. Of those individuals, three were compound heterozygous for the variant and a pathogenic variant confirmed in trans (Oliver-Petit I et al., PMID: 34248839; Stranneheim H et al., PMID: 33726816) and four were homozygous for the variant (Acar S et al., PMID: 34780050; Polle OG et al., PMID: 34484748; van de Graaf SA et al., PMID: 10403171). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.13% in the European non-Finnish population with no homozygotes. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to TG function. Functional studies show that this variant results in altered splicing with a reduction of exon 3 inclusion, indicating that this variant may impact protein function (Bastarache L et al., PMID: 29590070). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by six submitters, and pathogenic or likely pathogenic by six submitters. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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