ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.572G>A (p.Arg191Gln) (rs746219370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203356 SCV001218261 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 191 of the MMAB protein (p.Arg191Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs746219370, ExAC 0.002%). This variant has been observed in several individuals affected with methylmalonic aciduria cobalamin B type (PMID: 16410054, 27591164, 23707710, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 219006). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.Arg191 amino acid residue in MMAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27591164, 23707710, 20556797, 30022420). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000203356 SCV000258530 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2016-01-07 no assertion criteria provided literature only
Baumgartner lab,University Children's Hospital Zurich RCV000203356 SCV001738802 pathogenic Vitamin B12-responsive methylmalonic acidemia type cblB 2021-06-01 no assertion criteria provided clinical testing

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