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

dbSNP: rs773059864

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667435	SCV000791878	uncertain significance	Methylmalonic aciduria, cblB type	2017-05-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667435	SCV001574360	pathogenic	Methylmalonic aciduria, cblB type	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the MMAB protein (p.Arg186Gln). This variant is present in population databases (rs773059864, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of cobalamin B type methylmalonic aciduria (PMID: 16410054, 33453710, 33552909, 34796408). 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 with a positive predictive value of 80%. 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, 16439175, 19625202). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017714	SCV004848740	likely pathogenic	Methylmalonic acidemia	2022-08-26	criteria provided, single submitter	clinical testing	The p.Arg186Gln variant in MMAB has been reported in the homozygous state in 3 individuals with methylmalonic acidemia (Lerner-Ellis 2006 PMID: 16410054, Kiykim 2021 PMID: 33552909). It has also been reported in ClinVar (Variation ID 552212) and it has been identified in 2/67960 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg186Trp) has been identified in individuals with methylmalonic acidemia and is classified as pathogenic by several clinical laboratories in ClinVar and they occur in one of highly conserved residus, which are thought to be involved in the formation of the active site where many pathogenic variants in this gene have been identified (Lerner-Ellis 2006 PMID: 16410054). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal autosomal methylmalonic acidemia. ACMG/AMP criteria provided: PM2_Supporting, PP3, PM5, PM3, PM1.
Baumgartner lab, University Children's Hospital Zurich	RCV000667435	SCV001738796	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000667435	SCV002088690	likely pathogenic	Methylmalonic aciduria, cblB type	2020-10-13	no assertion criteria provided	clinical testing