ClinVar

Description

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.