ClinVar Genomic variation as it relates to human health

Variant summary: TPO c.1477G>A (p.Gly493Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251336 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TPO causing Deficiency Of Iodide Peroxidase (5.6e-05 vs 0.0071), allowing no conclusion about variant significance. c.1477G>A has been reported in the literature in multiple individuals affected with congenital hypothyroidism, and some were compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15745925, 21490078, 11874711, 34539567, 33368191). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

ClinVar contains an entry for this variant (Variation ID: 1064772). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TPO protein function. This missense change has been observed in individual(s) with clinical features of total iodide organification defect and/or congenital hypothyroidism (PMID: 11874711, 15745925, 17381485, 21490078, 33368191, 34539567). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778515113, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 493 of the TPO protein (p.Gly493Ser).