Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000778228 | SCV000914396 | uncertain significance | Disorders of Intracellular Cobalamin Metabolism | 2018-10-15 | criteria provided, single submitter | clinical testing | The MTR c.250-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for disorders of intracellular cobalamin metabolism. |
| Invitae | RCV003514412 | SCV004344514 | likely pathogenic | Methylcobalamin deficiency type cblG | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 2 of the MTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MTR are known to be pathogenic (PMID: 9683607, 12068375). This variant is present in population databases (rs145939391, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 631597). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |