Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000202581 | SCV000800633 | uncertain significance | Methylmalonic aciduria, cblB type | 2017-12-07 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000202581 | SCV001138810 | likely pathogenic | Methylmalonic aciduria, cblB type | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001804941 | SCV002051241 | uncertain significance | not specified | 2021-12-18 | criteria provided, single submitter | clinical testing | Variant summary: MMAB c.548A>T (p.His183Leu) results in a non-conservative amino acid change located in the Cobalamin adenosyltransferase-like domain (IPR016030) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249390 control chromosomes. c.548A>T has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Methylmalonic Acidemia, cblB type (example. Brasil_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a destabilizing effect and a mild reduction of adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR) activity and half-life (Brasil_2015). Two clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=2 including OMIM as P; VUS. n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Invitae | RCV000202581 | SCV003514773 | pathogenic | Methylmalonic aciduria, cblB type | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 183 of the MMAB protein (p.His183Leu). This variant is present in population databases (rs752866643, gnomAD 0.009%). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin B type (PMID: 24813872, 30041674). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218328). 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 MMAB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MMAB function (PMID: 24813872). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000202581 | SCV004193135 | likely pathogenic | Methylmalonic aciduria, cblB type | 2023-10-14 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000202581 | SCV000257524 | pathogenic | Methylmalonic aciduria, cblB type | 2015-06-01 | no assertion criteria provided | literature only |