Submissions for variant NM_052845.4(MMAB):c.571C>T (p.Arg191Trp)

gnomAD frequency: 0.00004  dbSNP: rs376128990

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414492	SCV000331820	pathogenic	not provided	2015-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000414492	SCV000491107	pathogenic	not provided	2020-02-24	criteria provided, single submitter	clinical testing	Functional analysis found that R191W has decreased enzyme activity compared to wild type (Zhang et al., 2006; Jorge-Finnigan et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17948227, 17957493, 12471062, 25087612, 23674520, 16410054, 20556797, 16439175, 27591164, 30022420, 30712249)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000202597	SCV000746327	pathogenic	Methylmalonic aciduria, cblB type	2017-12-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000202597	SCV001810503	pathogenic	Methylmalonic aciduria, cblB type	2021-07-22	criteria provided, single submitter	clinical testing
Invitae	RCV000202597	SCV002243059	pathogenic	Methylmalonic aciduria, cblB type	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the MMAB protein (p.Arg191Trp). This variant is present in population databases (rs376128990, gnomAD 0.01%). This missense change has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 12471062, 23707710, 27591164, 30712249). ClinVar contains an entry for this variant (Variation ID: 218324). 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%. Experimental studies have shown that this missense change affects MMAB function (PMID: 12471062, 20556797). 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: 16410054, 23707710, 27591164; Invitae). 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.
Ambry Genetics	RCV002515492	SCV003686105	pathogenic	Inborn genetic diseases	2021-09-24	criteria provided, single submitter	clinical testing	The c.571C>T (p.R191W) alteration is located in exon 7 (coding exon 7) of the MMAB gene. This alteration results from a C to T substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a tryptophan (W). This mutation has been reported in the compound heterozygous and homozygous states in multiple individuals with methylmalonic aciduria cblB complementation type (Devi, 2017; Dobson, 2002; Lerner-Ellis, 2006; Martínez, 2005; eker Ylmaz, 2021; Shafaat, 2018). Functional studies show that this alteration impairs enzyme activity (Jorge-Finnigan, 2010; Lerner-Ellis, 2006; Zhang, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000202597	SCV004193133	pathogenic	Methylmalonic aciduria, cblB type	2023-10-19	criteria provided, single submitter	clinical testing
OMIM	RCV000202597	SCV000257520	pathogenic	Methylmalonic aciduria, cblB type	2010-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000202597	SCV000258529	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Counsyl	RCV000202597	SCV000789983	likely pathogenic	Methylmalonic aciduria, cblB type	2017-10-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000202597	SCV001459238	pathogenic	Methylmalonic aciduria, cblB type	2020-09-16	no assertion criteria provided	clinical testing
Baumgartner lab, University Children's Hospital Zurich	RCV000202597	SCV001738801	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing