Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000518274 | SCV000616211 | uncertain significance | not specified | 2017-04-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001857934 | SCV002234183 | pathogenic | Familial amyloid neuropathy | 2021-09-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu74 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. 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: 448842). This variant is also known as Glu54Gln. This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 25044787, 27519456, 31718691, 32000831). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 74 of the TTR protein (p.Glu74Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. |
| Ambry Genetics | RCV002431479 | SCV002729588 | likely pathogenic | Cardiovascular phenotype | 2019-02-01 | criteria provided, single submitter | clinical testing | The p.E74Q variant (also known as c.220G>C and E54Q), located in coding exon 3 of the TTR gene, results from a G to C substitution at nucleotide position 220. The glutamic acid at codon 74 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in two individuals with restrictive cardiomyopathy, biopsies documenting the presence of amyloid via Congo red staining, and a family history of a parent with cardiomyopathy. One individual also had progressive peripheral sensory motor polyneuropathy and autonomic dysfunction while the second individual had carpal tunnel syndrome; her parent with cardiomyopathy also had severe sensorimotor neuropathy (Rowczenio DM et al. Hum. Mutat., 2014 Sep;35:E2403-12). This amino acid position is highly 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. |