Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002444876 | SCV002611478 | uncertain significance | Cardiovascular phenotype | 2020-07-14 | criteria provided, single submitter | clinical testing | The p.E109D variant (also known as c.327G>T), located in coding exon 3 of the TTR gene, results from a G to T substitution at nucleotide position 327. The glutamic acid at codon 109 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was identified in an individual with axonal polyneuropathy, distal paresthesia, weakness in limbs, and weight loss (Chao HC et al. Ann Clin Transl Neurol, 2019 May;6:913-922). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003626611 | SCV004509611 | pathogenic | Amyloidosis, hereditary systemic 1 | 2023-02-26 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Glu109 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301926, 28635949). 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. 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: 235066). This missense change has been observed in individual(s) with clinical features of TTR-related conditions (PMID: 31139689; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 109 of the TTR protein (p.Glu109Asp). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223752 | SCV000280536 | uncertain significance | not specified | 2015-09-18 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu89Asp (c.327G>T) in the TTR gene. The variant is novel. It has not been reported in association with familial amyloidosis in the literature, to the best of our knowledge. However, two other variants at this amino acid position (109, also referred to as 89 on the historical transcript) have been reported in patients with familial amyloidosis (see below for more detail). In silico analysis with PolyPhen 2 and Mutation taster predict the variant to be damaging. The Glutamine at codon 109 (using the current transcript, NM000371.3) is conserved across species, except for in lamprey (Q). Other variants have been reported in association with disease at this codon (Glu89Gln and Glu89Lys): A different variant at the same residue, p.Glu89Gln, was reported in an association with familial amyloidosis in at least 12 unrelated individuals, mainly of Italian descent, with amyloidosis in the literature. Glu89Gln was first reported in an Italian family with familial amyloidosis (Almeida et al. 1992). In this paper, the affected individuals had polyneuropathy and cardiomyopathy. Amyloidosis was confirmed by skin or nerve biopsy in at least 2 family members with symptoms. After testing 11 individuals in this family, the authors found the p.Glu89Gln variant in 3 individuals with amyloidosis and 8 asymptomatic relatives. One affected relative was not available for genetic testing. The variant was never found to fail to segregate in this family. Cappellari et al. 2011 identified the p.Glu89Gln variant in trans with the established pathogenic variant, TTR p.Val122Ile. Finally, Rapezzi et al. 2013 and Ihse et al. 2013 report that this Glu89Gln variant was seen in 9 unrelated families with familial amyloidosis, including 40 total patients (including both cardiac and neurologic involvement). Another variant at the same residue (p.Glu89Lys, also called p.Glu109Lys on the longer TTR transcript) was identified in a 57 year old man who presented with polyneuropathy, severe autonomic dysfunction and cardiomyopathy (Nakamura et al. 2000). There is a variant reported one codon downstream, p.His90Asn (His110Asn on the longer transcript) that is reported in ClinVar with conflicting assessments; LabCorp considers it to be likely benign, LMM considers it to be a VUS, and there is an entry from OMIM in reference to a paper in the literature. This His90Asn variant was seen in 80 individuals from the ExAC database, which may be too common to cause familial amyloidosis. I contacted several genetic testing laboratories regarding this patient’s TTR p.Glu109Asp variant. None of these laboratories report having seen this variant before (personal communication, laboratory genetic counselors, September 18, 2015). In total the variant has not been seen in ~60,000 individuals from publicly available population datasets. There is no variation at this codon listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of September 17, 2015). Note that this dataset does not match the patient’s ancestry (Chinese). There is also no variation at this codon listed in dbSNP or 1000Genomes (as of September 17, 2015). There is no variation at codon 109 (using the longer transcript) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of September 17, 2015). The Veternas General Hospital-Taipei genetic testing laboratory reports that they directly sequenced “more than 50 normal subjects” for this variant. Note: Given there is a historically used transcript and current major transcript for the TTR gene, this variant can be referred to in two ways in the literature: Glu89Asp or Glu109Asp. The laboratory reports this variant to be on the longer TTR transcript, NM000371.3, which corresponds to p.Glu109Asp (c.327G>T). The partial transcript, which does not contain the 20 amino acid signal peptide, corresponds to p.Glu89Asp. Because this transcript was used historically, many of the nearby disease associated variants are listed in reference to the variant when it is described as p.Glu89Asp. |