ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 94 of the TTR protein (p.Asp94His). This variant is present in population databases (rs730881164, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hATTR amyloidosis and/or hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 29121657, 32376792, 34658264; Invitae). ClinVar contains an entry for this variant (Variation ID: 181695). 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 expected to disrupt TTR protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.D94H variant (also known as c.280G>C), located in coding exon 3 of the TTR gene, results from a G to C substitution at nucleotide position 280. The aspartic acid at codon 94 is replaced by histidine, an amino acid with similar properties. This variant was first reported in 7 German individuals with no family history of amyloidosis (Umechi T et al. Amyloid, 1994;1(3):149-53). This variant was reported in an individual with hypertrophic cardiomyopathy in conjunction with a variant in another cardiac gene, and has also been detected in a Charcot-Marie-Tooth disease cohort (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Volodarsky M et al. J Med Genet. 2021 04;58(4):284-288). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Reported in one individual with hypertrophic cardiomyopathy (HCM) and one individual with suspected Charcot-Marie-Tooth disease (CMT) (PMID: 29121657, 32376792); Identified in 7 out of 4,000 pregnant German women with no family history of amyloidosis or thyroid disorder; reported as a common variant in the German population; denoted as D74H by alternative nomenclature (Uemichi et al. (1994) Amyloid: The Journal of Protein Folding Disorders 1 (3) :149-53 (http://www.tandfonline.com/doi/abs/10.3109/13506129409148445)); 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, 32376792, 34658264, 29121657)