Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001808154 | SCV002058684 | likely pathogenic | Familial amyloid neuropathy | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TTR related disorder (PMID:10211412, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013426, PMID:24101130,2349941, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.689, 3CNET: 0.976, PP3_P). A missense variant is a common mechanism associated with Amyloidosis (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Invitae | RCV001808154 | SCV004297830 | pathogenic | Familial amyloid neuropathy | 2023-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 142 of the TTR protein (p.Val142Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 10211412, 30595768). This variant is also known as p.Val122Ala. ClinVar contains an entry for this variant (Variation ID: 1333466). 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 with a positive predictive value of 95%. This variant disrupts the p.Val142 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). 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. |