ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.548A>T (p.His183Leu)

gnomAD frequency: 0.00002  dbSNP: rs752866643
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Total submissions: 6
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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, LabCorp 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

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