ClinVar Genomic variation as it relates to human health

Variant summary: c.302C>T affects a non-conserved nucleotide, resulting in amino acid change from Ala to Val. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was not found in 121370 control chromosomes. The variant of interest was reported in at least 1 kindred presented with cardiac amyloidosis (Benson_2007) with limited information on segregation. This variant has not, to our knowledge, been evaluated for functional impact by in vivo/vitro studies by the time of evaluation. Another alteration of the same codon, p.A101T, have been reported in association with cardiac amyloidosis. It is possible that this variant is pathogenic, however, more clinical and segregation date needed to classify this variant with confidence. Taken together, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as A81V; This variant is associated with the following publications: (PMID: Holcman_2021_Abstract, 17554795, 25044787, 32789836, 30328212, 34024775)

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the TTR protein (p.Ala101Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 25044787, 32789836, 34024775). This variant is also known as Ala81Val. ClinVar contains an entry for this variant (Variation ID: 495842). 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%. This variant disrupts the p.Ala101 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The TTR c.302C>T; p.Ala101Val variant (rs1555631417), also known as Ala81Val in the mature protein, is reported in the literature in several individuals affected with transthyretin-related amyloidosis (Benson 2007, Chen 2021, Gawor 2022). This variant is also reported in ClinVar (Variation ID: 495842). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.301G>A; p.Ala101Thr) have been reported in individuals with transthyretin-related amyloidosis (Connors 2003), but clinical significance is uncertain. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.752). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Benson MD et al. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23. PMID: 17554795. Chen Z et al. Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore. J Neuromuscul Dis. 2021;8(4):723-733. PMID: 34024775. Connors LH et al. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. 2003 Sep;10(3):160-84. PMID: 14640030. Gawor M et al. Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis. Cardiol J. 2022;29(6):985-993. PMID: 32789836.

The p.A101V variant (also known as c.302C>T), located in coding exon 3 of the TTR gene, results from a C to T substitution at nucleotide position 302. The alanine at codon 101 is replaced by valine, an amino acid with similar properties. This variant, which is also known as p.A81V, has been reported in individuals with transthyretin (TTR) amyloidosis, including cardiomyopathy and polyneuropathy (Benson MD et al. Muscle Nerve, 2007 Oct;36:411-23; Rowczenio D et al. Hum Mutat, 2019 Jan;40:90-96; Tseng H et al. Acta Cardiol Sin, 2021 Sep;37:549-553; Gawor M et al. Cardiol J, 2022 Aug;29:985-993; Sha Q et al. ESC Heart Fail, 2023 Oct;[ePub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.