ClinVar Miner

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

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Total submissions: 4
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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.
GeneReviews RCV000203392 SCV000258528 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2016-01-07 no assertion criteria provided literature only

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