Submissions for variant NM_052845.4(MMAB):c.569G>A (p.Arg190His)

dbSNP: rs756414548

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186018	SCV000238980	pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing	The R190H variant is a conservative amino acid substitution as these residues share similar properties, and are less likely to impact secondary structure. This change occurs at a residue that is conserved across species. In silico analysis predicts this mutation is probably damaging to the protein structure/function. Mutations at this residue (R190C) and nearby residues (R186Q, R191W, R191Q) have been reported in association with methylmalonic aciduria, supporting the functional importance of this residue and this region of the protein. The R190H mutation in the MMAB gene has been reported previously in association with methylmalonic aciduria (Lerner-Ellis et al., 2006). The R190H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R190H as a disease-causing mutation. This variant has been observed to be maternally inherited.
Counsyl	RCV000203392	SCV000791445	likely pathogenic	Methylmalonic aciduria, cblB type	2017-05-16	criteria provided, single submitter	clinical testing
Invitae	RCV000203392	SCV000942969	pathogenic	Methylmalonic aciduria, cblB type	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the MMAB protein (p.Arg190His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 203819). 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: 16439175, 19625202). This variant disrupts the p.Arg190 amino acid residue in MMAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16410054, 19625202, 24059531, 29039164, 29197662). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420745	SCV001623088	pathogenic	Methylmalonic acidemia	2021-04-21	criteria provided, single submitter	clinical testing	Variant summary: MMAB c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Cobalamin adenosyltransferase-like of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248806 control chromosomes. c.569G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2006). In experimental studies, the variant has been shown to result in decreased stability, significantly decreased affinity for AdoCbl, the product of the adenosylation reaction, and therefore completely inactive enzyme (Brasil_2018, Zhang_2006, Zhang_2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as pathogenic/likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000203392	SCV004193147	pathogenic	Methylmalonic aciduria, cblB type	2023-04-13	criteria provided, single submitter	clinical testing
GeneReviews	RCV000203392	SCV000258528	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Baumgartner lab, University Children's Hospital Zurich	RCV000203392	SCV001738800	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing