rs730881164

Description

The D94H variant, also denoted as D74H by alternative nomenclature, has been reported as a common variant in the German population as it was identified in 7 out of 4,000 pregnant women with no family history of amyloidosis or thyroid disorder (Uemichi et al., 1994; 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: 14640030, 29121657, 32376792)

This sequence change replaces aspartic acid with histidine at codon 94 of the TTR protein (p.Asp94His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs730881164, ExAC 0.004%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy, however in that individual additional variants in other genes associated with cardiomyopathy were detected (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181695). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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: TTR c.280G>C (p.Asp94His) (legacy name p.Asp74His) results in a non-conservative amino acid change located in the Transthyretin/hydroxyisourate hydrolase domain (IPR023416) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251446 control chromosomes. The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTR causing Transthyretin Amyloidosis phenotype (3.1e-05), strongly suggesting that the variant is benign. c.280G>C has been reported in the literature as a non-amyloidogenic variant that was found in seven unrelated families with no personal history of amyloidosis nor thyroid disorders and was considered as a frequent polymorphism in the German population (example, Uemichi_1994). It has subsequently been reported in settings of multigene panel testing within within cohorts of individuals with hypertrophic cardiomyopathy (HCM) and Charcot-Marie -Tooth disease (example, Viswanathan_2017, Volodarsky_2021). Furthermore, recent reports have categorized this among TTR gene variants that do not affect function (example, Pueyo_2019). In summary, these report(s) do not provide unequivocal conclusions about association of the variant with Transthyretin Amyloidosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.