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

gnomAD frequency: 0.00071  dbSNP: rs142698837

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501874	SCV000597479	uncertain significance	not specified	2016-11-07	criteria provided, single submitter	clinical testing
Center for Precision Medicine, Vanderbilt University Medical Center	RCV000760170	SCV000889989	pathogenic	Iodotyrosyl coupling defect	2018-03-16	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000764740	SCV000895877	uncertain significance	Iodotyrosyl coupling defect; Autoimmune thyroid disease, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000501874	SCV000966240	uncertain significance	not specified	2018-07-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly77Ser variant in TG has been reported in the homozygous state in 3 individuals with co ngenital hypothyroidism (van de Graaf 1999) and has been reported in ClinVar (Va riation ID: 436996). This variant has been identified in 0.13% (167/126550) of E uropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs142698837). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. In vitro functional studies suggest that the p.Gly77Ser variant leads to th e use of an alternative splice site (Bastarache 2018); however, these types of a ssays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this varia nt is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PS3_Supporting, PM3_Su pporting.
Illumina Laboratory Services, Illumina	RCV000760170	SCV001324740	uncertain significance	Iodotyrosyl coupling defect	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001729618	SCV002061141	pathogenic	not provided	2025-03-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23933148, 34426522, 29590070, 33726816, 34484748, 34248839, 10403171, 34780050, 36884306)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001729618	SCV003254958	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 77 of the TG protein (p.Gly77Ser). This variant is present in population databases (rs142698837, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital hypothyroidism (PMID: 10403171, 29590070, 34248839). ClinVar contains an entry for this variant (Variation ID: 436996). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 29590070). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000760170	SCV003819450	uncertain significance	Iodotyrosyl coupling defect	2019-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155217	SCV003844786	likely pathogenic	TG-related disorder	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: TG c.229G>A (p.Gly77Ser) results in a non-conservative amino acid change located in the Thyroglobulin type-1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing (Bastarache_2018). The variant allele was found at a frequency of 0.00076 in 251242 control chromosomes with no homozygous occurrences in the database (gnomad). c.229G>A has been reported in the literature in multiple individuals affected with TG-Related Disorders, including consanguineous patients who have the variant in the homozygous state (vandeGraaf_TG_Bioch_1999, Acar_2022) and patients who have the variant in the compound heterozygous state with other missense or nonsense variants, with at least one confirmed as being in-trans (Machiavelli_2009, Oliver-Petit_2021). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Two submitters classified the variants as likely pathogenic/pathogenic while five classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000760170	SCV004175302	likely pathogenic	Iodotyrosyl coupling defect	2022-12-22	criteria provided, single submitter	clinical testing	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).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000760170	SCV005685136	uncertain significance	Iodotyrosyl coupling defect	2024-12-18	criteria provided, single submitter	clinical testing	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000764740	SCV006056556	uncertain significance	Iodotyrosyl coupling defect; Autoimmune thyroid disease, susceptibility to, 3	2023-03-10	criteria provided, single submitter	research
Clinical Genetics, Academic Medical Center	RCV001729618	SCV001979058	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729618	SCV001980342	likely pathogenic	not provided		no assertion criteria provided	clinical testing