ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.569G>A (p.Arg190His) (rs756414548)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186018 SCV000238980 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The R190H variant is a conservative amino acid substitution as these residues share similar properties, and are less likely to impact secondary structure. This change occurs at a residue that is conserved across species. In silico analysis predicts this mutation is probably damaging to the protein structure/function. Mutations at this residue (R190C) and nearby residues (R186Q, R191W, R191Q) have been reported in association with methylmalonic aciduria, supporting the functional importance of this residue and this region of the protein. The R190H mutation in the MMAB gene has been reported previously in association with methylmalonic aciduria (Lerner-Ellis et al., 2006). The R190H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R190H as a disease-causing mutation. This variant has been observed to be maternally inherited.
Counsyl RCV000203392 SCV000791445 likely pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2017-05-16 criteria provided, single submitter clinical testing
Invitae RCV000203392 SCV000942969 uncertain significance Vitamin B12-responsive methylmalonic acidemia type cblB 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 190 of the MMAB protein (p.Arg190His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs756414548, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another MMAB variant in in individuals affected with methylmalonic aciduria cobalamin B type (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 203819). Experimental studies have shown that this missense change disrupts protein function (PMID: 16439175, 19625202). This variant disrupts the p.Arg190 amino acid residue in MMAB. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16410054), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420745 SCV001623088 pathogenic Methylmalonic acidemia 2021-04-21 criteria provided, single submitter clinical testing Variant summary: MMAB c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Cobalamin adenosyltransferase-like 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 4e-06 in 248806 control chromosomes. c.569G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2006). In experimental studies, the variant has been shown to result in decreased stability, significantly decreased affinity for AdoCbl, the product of the adenosylation reaction, and therefore completely inactive enzyme (Brasil_2018, Zhang_2006, Zhang_2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as pathogenic/likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000203392 SCV000258528 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2016-01-07 no assertion criteria provided literature only
Baumgartner lab,University Children's Hospital Zurich RCV000203392 SCV001738800 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2021-06-01 no assertion criteria provided clinical testing

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