ClinVar Genomic variation as it relates to human health

p.Arg5His in exon 1 of TTR: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >15 mammals, including chimpanzee, have a histidine (His) at this position. Thi s variant has been identified in 21/126636 European chromosomes, including 1 hom ozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs138657343).

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Reported in an individual with HCM who also harbored a variant in the MYBPC3 gene in published literature (Viswanathan et al., 2017); however, no segregation studies were described; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27249223, 31659433, 29121657, 32674397)

The TTR c.14G>A variant is predicted to result in the amino acid substitution p.Arg5His. This variant was reported in an individual with Cardiomyopathy, hypertrophic (Table S3 Viswanathan et al. 2017. PubMed ID: 29121657) and in an individual with hereditary amyloidosis (Auer-Grumbach et al. 2020. PubMed ID: 32674397). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-29171879-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the TTR protein (p.Arg5His). This variant is present in population databases (rs138657343, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TTR-related conditions (PMID: 29121657, 32674397). ClinVar contains an entry for this variant (Variation ID: 181697). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

The TTR c.14G>A; p.Arg5His variant (rs138657343) is reported in the literature in an individual affected with hereditary transthyretin amyloidosis (Auer-Grumbach 2020) as well as in an individual with hypertrophic cardiomyopathy (Viswanathan 2017). This variant is also reported in ClinVar (Variation ID: 181697). It is found in the general population with an overall allele frequency of 0.013% (36/282806 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.268). However, given the lack of clinical and functional data, the significance of the p.Arg5His variant is uncertain at this time. References: Auer-Grumbach M et al. Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots. J Clin Med. 2020 Jul 14;9(7):2234. PMID: 32674397. Viswanathan SK et al. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS One. 2017 Nov 9;12(11):e0187948. PMID: 29121657.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant classified as Uncertain significance and reported on 11-03-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.