Submissions for variant NM_052845.4(MMAB):c.403G>A (p.Ala135Thr)

gnomAD frequency: 0.00272  dbSNP: rs35648932

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482151	SCV000568147	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing	The A135T variant in the MMAB gene has previously been reported in individuals with methylmalonic acidemia (MMA) cblB type who also harbored the R191W pathogenic variant and two of these patients were also reported to be heterozygous for a Y219C variant in MMAB; the phase of these variants was not determined (Dobson et al., 2002; Lerner-Ellis et al., 2006). The A135T variant is observed in 83/6162 (1.4%) alleles from individuals of African background, including 2 homozygous individuals in the ExAC dataset (Lek et al., 2016). The A135T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203394	SCV000763804	benign	Methylmalonic aciduria, cblB type	2024-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271462	SCV002556220	benign	not specified	2022-06-28	criteria provided, single submitter	clinical testing	Variant summary: MMAB c.403G>A (p.Ala135Thr) results in a non-conservative amino acid change located in the cobalamin adenosyltransferase-like domain (IPR016030) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 241100 control chromosomes, predominantly at a frequency of 0.0096 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in MMAB causing Methylmalonic Acidemia phenotype (0.0017), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.403G>A has been reported in the literature in at least two individuals affected with Methylmalonic Acidemia without strong evidence for causality (e.g. Dobson_2002, Lerner-Ellis_2006). These reports do not provide unequivocal conclusions about association of the variant with Methylmalonic Acidemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (Benign n=2, VUS n=1, pathogenic n=1). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000482151	SCV004131848	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	MMAB: BS2
GeneReviews	RCV000203394	SCV000258525	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Natera, Inc.	RCV000203394	SCV001455425	benign	Methylmalonic aciduria, cblB type	2020-01-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967547	SCV004785082	likely benign	MMAB-related disorder	2023-10-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).