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

gnomAD frequency: 0.00003  dbSNP: rs746219370

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203356	SCV001218261	pathogenic	Methylmalonic aciduria, cblB type	2023-12-19	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 191 of the MMAB protein (p.Arg191Gln). This variant is present in population databases (rs746219370, gnomAD 0.003%). This missense change has been observed in individual(s) with methylmalonic aciduria cobalamin B type (PMID: 16410054, 23707710, 27591164; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 219006). 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 not expected to disrupt MMAB protein function with a negative predictive value of 80%. 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: 20556797, 23707710, 27591164, 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.
GeneDx	RCV002281067	SCV002569816	pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Brasil et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30973671, 23707710, 16410054, 31589614, 29197662, 20301409, 27591164)
Ambry Genetics	RCV002517365	SCV003630590	pathogenic	Inborn genetic diseases	2022-07-05	criteria provided, single submitter	clinical testing	The c.572G>A (p.R191Q) alteration is located in exon 7 (coding exon 7) of the MMAB gene. This alteration results from a G to A substitution at nucleotide position 572, causing the arginine (R) at amino acid position 191 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (5/279944) total alleles studied. The highest observed frequency was <0.01% (4/128276) of European (non-Finnish) alleles. This alteration has been identified in the compound heterozygous and homozygous state in multiple individuals with methylmalonic aciduria (Lerner-Ellis, 2006; Illson, 2013; Devi, 2017; Forny, 2021). This amino acid position is highly conserved in available vertebrate species. Experimental studies have shown this variant causes destabilization and impaired oligomerization of the protein (Brasil, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000203356	SCV004193141	pathogenic	Methylmalonic aciduria, cblB type	2024-03-14	criteria provided, single submitter	clinical testing
GeneReviews	RCV000203356	SCV000258530	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Baumgartner lab, University Children's Hospital Zurich	RCV000203356	SCV001738802	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing