ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

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.

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).