Submissions for variant NM_052845.4(MMAB):c.656A>G (p.Tyr219Cys)

gnomAD frequency: 0.00004  dbSNP: rs765547005

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424166	SCV000520445	uncertain significance	not provided	2017-07-20	criteria provided, single submitter	clinical testing	The Y219C variant has previously been reported in association with methylmalonic acidemia (MMA), cblB type in two individuals who were also heterozygous for two other variants in the MMAB gene; the phase of these variants was not determined (Lerner-Ellis et al., 2006). The Y219C 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 in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Counsyl	RCV000203386	SCV000800739	uncertain significance	Methylmalonic aciduria, cblB type	2018-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509300	SCV002819802	uncertain significance	not specified	2022-12-24	criteria provided, single submitter	clinical testing	Variant summary: MMAB c.656A>G (p.Tyr219Cys) 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 2.4e-05 in 251446 control chromosomes (gnomAD). c.656A>G has been reported in the literature as a complex genotype in individuals affected with Methylmalonic Aciduria, cblB type: these individuals carried a second pathogenic variant and a benign/VUS variant (Lerner-Ellis_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV000203386	SCV004283178	likely pathogenic	Methylmalonic aciduria, cblB type	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 219 of the MMAB protein (p.Tyr219Cys). This variant is present in population databases (rs765547005, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of cobalamin B deficiency (PMID: 16410054; 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: 219007). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews	RCV000203386	SCV000258531	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Natera, Inc.	RCV000203386	SCV001459236	uncertain significance	Methylmalonic aciduria, cblB type	2020-09-16	no assertion criteria provided	clinical testing