ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.227A>G (p.His76Arg)

gnomAD frequency: 0.00001  dbSNP: rs78230119
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001237948 SCV001410740 uncertain significance Amyloidosis, hereditary systemic 1 2023-05-09 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 963852). This variant is also known as p.His56Arg. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 17554795). This variant is present in population databases (rs78230119, gnomAD 0.007%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 76 of the TTR protein (p.His76Arg).
Ambry Genetics RCV002447188 SCV002734677 uncertain significance Cardiovascular phenotype 2023-04-17 criteria provided, single submitter clinical testing The p.H76R variant (also known as c.227A>G), located in coding exon 3 of the TTR gene, results from an A to G substitution at nucleotide position 227. The histidine at codon 76 is replaced by arginine, an amino acid with highly similar properties. This alteration (also referred to as p.H56R) has reportedly been associated with transthyretin (TTR) amyloidosis and related cardiomyopathy; however, clinical details are limited (Saraiva MJ. Hum Mutat, 2001 Jun;17:493-503; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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