ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.557G>A (p.Arg186Gln) (rs773059864)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667435 SCV000791878 uncertain significance Vitamin B12-responsive methylmalonic acidemia type cblB 2017-05-30 criteria provided, single submitter clinical testing
Invitae RCV000667435 SCV001574360 likely pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2020-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 186 of the MMAB protein (p.Arg186Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs773059864, ExAC 0.002%). This variant has been observed in individual(s) with cobalamin B type methylmalonic aciduria (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 552212). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg186 amino acid residue in MMAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12471062, 16410054, 19625202,16439175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baumgartner lab,University Children's Hospital Zurich RCV000667435 SCV001738796 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2021-06-01 no assertion criteria provided clinical testing

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