Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000254885 | SCV000322292 | pathogenic | not provided | 2019-12-30 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate R452C interferes with the cofactor and succinyl-CoA binding ability of the ALAS2 protein (Bishop et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7592563, 21800356, 10029606, 24323989, 21309041, 22740690, 16343269, 21252495, 16540354, 22983749, 32605921) |
| Invitae | RCV000254885 | SCV003445243 | pathogenic | not provided | 2023-06-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg452 amino acid residue in ALAS2. Other variant(s) that disrupt this residue have been observed in individuals with ALAS2-related conditions (PMID: 7592563, 21309041, 32297424), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ALAS2 function (PMID: 22740690). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. ClinVar contains an entry for this variant (Variation ID: 10485). This missense change has been observed in individuals with X-linked congenital sideroblastic anemia (PMID: 7592563, 21309041, 32297424). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 452 of the ALAS2 protein (p.Arg452Cys). |
| OMIM | RCV000011231 | SCV000031458 | pathogenic | X-linked sideroblastic anemia 1 | 1999-03-01 | no assertion criteria provided | literature only |