Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780426 | SCV000917670 | likely pathogenic | Methylmalonic acidemia | 2018-04-16 | criteria provided, single submitter | clinical testing | Variant summary: MMAB c.584G>A (p.Arg195His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Jorge-Finnigan_2010). The variant was observed with an allele frequency of 8.2e-06 in 243566 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MMAB causing Methylmalonic Acidemia (8.2e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.584G>A, was observed in two siblings, one presenting with Methylmalonic Acidemia, while the sibling with the same genotype was asymptomatic (Jorge-Finnigan_2010). Multiple publications have functionally assessed the variant and observed the variant to affect splicing, but does produce a limited amount of wild type protein (Jorge-Finnigan_2010), along with presenting functional implications on proper MMAB protein function (Brasil_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV000202574 | SCV003441168 | uncertain significance | Methylmalonic aciduria, cblB type | 2022-05-17 | criteria provided, single submitter | clinical testing | This sequence change affects codon 195 of the MMAB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MMAB protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs756195708, gnomAD 0.003%). This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20556797). ClinVar contains an entry for this variant (Variation ID: 218322). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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 variant is associated with altered splicing resulting in unknown protein product impact (PMID: 20556797). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV000202574 | SCV004193148 | likely pathogenic | Methylmalonic aciduria, cblB type | 2023-02-20 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000202574 | SCV000257518 | pathogenic | Methylmalonic aciduria, cblB type | 2010-09-01 | no assertion criteria provided | literature only | |
| Natera, |
RCV000202574 | SCV001459237 | likely pathogenic | Methylmalonic aciduria, cblB type | 2020-09-16 | no assertion criteria provided | clinical testing |