ClinVar Genomic variation as it relates to human health

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Identified in multiple unrelated patients with hypothyroidism in published literature, however the variant was also reported in family members with normal thyroid function and a GNAS variant was also report in one family (Camilot et al., 2005; DeMarco et al., 2009; Lado-Abeal et al., 2011); Published functional studies demonstrate a damaging effect with lower cAMP response to thyroid stimulating hormone (TSH) and a lower TSH binding capacity (DeMarco et al., 2009; Lado-Abeal et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21186955, 16060907, 18727713, 34919466, 33446056, 17705697, 30372544, 29237690, 32368696)

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 34 of the TSHR protein (p.Glu34Lys). This variant is present in population databases (rs45499704, gnomAD 0.04%). This missense change has been observed in individual(s) with TSHR-related conditions (PMID: 16060907, 30372544). ClinVar contains an entry for this variant (Variation ID: 886125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSHR protein function. Experimental studies have shown that this missense change affects TSHR function (PMID: 17705697, 18727713). 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: TSHR c.100G>A (p.Glu34Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 250254 control chromosomes, predominantly at a frequency of 0.0004 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.100G>A has been reported in the literature in several individuals affected with hypothyroidism (e.g., Camilot_2005, DeMarco_2009, Lado-Abeal_2011) as well as individuals with Graves disease (e.g., Colobran_2011), congenital heart disease (e.g., Edwards_2020), and hyperthyroidism (e.g., Patel_2019), however without strong evidence for causality in these cases. These reports therefore do not provide unequivocal conclusions about association of the variant with Hypothyroidism Due To TSH Receptor Mutations. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a modest decrease (approximately >50%-90%) in normal activity (e.g., DeMarco_2009, Lado-Abeal_2011). The following publications have been ascertained in the context of this evaluation (PMID: 16060907, 21642385, 18727713, 32368696, 21186955, 30372544). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.100G>A (p.E34K) alteration is located in exon 1 (coding exon 1) of the TSHR gene. This alteration results from a G to A substitution at nucleotide position 100, causing the glutamic acid (E) at amino acid position 34 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.