Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Medico- |
RCV002294539 | SCV002587004 | pathogenic | Amyloidosis, hereditary systemic 1 | 2022-10-22 | criteria provided, single submitter | clinical testing | The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was not found in the control populations from the gnomAD v2.1.1 project. There are three Pathogenic or Likely Pathogenic variants in the same codon: p.Glu74Gly (ClinVar Variation ID 811803), p.Glu74Ala (ClinVar Variation ID 1519705) and p.Glu74Lys (ClinVar Variation ID 636837). The variant has been reported several times in association with hereditary transthyretin amyloidosis, OMIM 105210, vATTR (PMID: 17554795;31169435). A rare alternative variant c.220_221delGAinsTT, which leads to the same amino acid change has also been reported in association with vATTR (PMID: 30328212). |
| Ambry Genetics | RCV002427758 | SCV002728715 | likely pathogenic | Cardiovascular phenotype | 2014-11-02 | criteria provided, single submitter | clinical testing | The p.E74L variant (also known as c.220_221delGAinsCT and E54L), located in coding exon 3 of the TTR gene, results from an in-frame deletion of GA and insertion of CT between nucleotide positions 220 and 221. This results in the substitution of the residue for a leucine residue at codon 74, an amino acid with dissimilar properties. Although this alteration has not been reported in the literature, two disease-causing mutations, p.E74G and p.E74K, have been described in the same codon. In addition, functional studies of those two disease-causing mutations indicate that this amino acid position is functionally important for tetramer stability and thyroxine binding (Miyata M et al. Biochemistry. 2010;49(1):114-23). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |