Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003555894 | SCV004293680 | pathogenic | not provided | 2024-01-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 603 of the MUT protein (p.Arg603Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 15781192, 17957493, 31622506, 36717752). ClinVar contains an entry for this variant (Variation ID: 1890). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 15781192). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the p.R603 amino acid residue in MUT. Other variant(s) that disrupt this residue have been observed in individuals with MUT-related conditions (PMID: 19375370, 34668645, 36717752), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000001967 | SCV000022125 | pathogenic | METHYLMALONIC ACIDURIA, mut(0) TYPE | 2007-12-01 | no assertion criteria provided | literature only |