rs121918243
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_015506.3(MMACHC):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015506.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.482G>A | p.Arg161Gln | missense_variant | 4/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.311G>A | p.Arg104Gln | missense_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.482G>A | p.Arg161Gln | missense_variant | 4/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | c.311G>A | p.Arg104Gln | missense_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000172 AC: 43AN: 249432Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135328
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727234
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74346
ClinVar
Submissions by phenotype
Cobalamin C disease Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2017 | Variant summary: The MMACHC c.482G>A (p.Arg161Gln) variant causes a missense change involving the alteration of a highly conserved nucleotide. The variant alters a cobalamin binding site on conserved domain MMACHC-like (PM1). 3/4 in silico tools predict deleterious outcome for this variant (SNP&GO was not used due to a low reliability index). In the functional studies mutant R161Q has a decreased ability to bind incoming CNCbl, which results in a decreased ability to reductively decyanate the CNCbl to the cob(II)alamin form used in the metabolic pathway (PS3). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.000195 (18/120402 chrs tested), predominantly in individuals of Latino descent (0.0013; 15/16508chrs tesed). The observed frequencies are extremely low and do not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (~0.0031) (PM2). The c.482G>A was identified heterozygously in an infant with combined methylmalonic aciduria and homocystinuria without availability of segregation data and parental clinical information; this patient also tested positive for a known pathogenic mutation in the same gene (phase is unknown). The variant of interest was reported in compound heterozygosity in multiple affected individuals presenting with biochemically confirmed dx of late-onset methylmalonic aciduria and homocystinuria and proven segregation within the family (PM3, PP1, PP4). At least one case of early-onset presentation has been reported in 2.5 months old infant homozygous for the variant of interest. The codon Arg161 appears to be a mutational hot spot, as other alteration of the same codon, c.481C>G (p.Arg161Gly) (PM5) and c.481C>T (p.Arg161*) were identified in patients with methylmalonic aciduria and homocystinuria. In addition, a clinical diagnostic laboratory/reputable database classified this variant as Pathogenic (PP5). Considering all evidence and ACMG guidelines, the variant was classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | research | Neurology Department, Peking University First Hospital | Apr 23, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the MMACHC protein (p.Arg161Gln). This variant is present in population databases (rs121918243, gnomAD 0.1%). This missense change has been observed in individuals with late-onset methylmalonic aciduria and homocystinuria (PMID: 16311595, 17853453, 19370762, 21055272, 22560872, 25687216, 26283149, 28218226). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1425). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. Experimental studies have shown that this missense change affects MMACHC function (PMID: 19700356, 20219402, 25809485). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | May 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Oct 25, 2018 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2020 | Published functional studies demonstrate reduced protein stability (Gherasim et al., 2015; Froese et al., 2009); 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: 20219402, 21055272, 26283149, 28693988, 19370762, 16311595, 31697851, 32099815, 19760748, 25367534, 25809485, 19914430, 18164228, 11320193, 17853453, 22560872, 25687216, 28218226, 29961769, 30863077, 31574870, 31203424, 30157807, 32208535, 29731766, 33822359, 31589614, 19700356, 32778825) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 25, 2017 | The MMACHC c.482G>A, p.Arg161Gln variant (rs121918243) has been previously reported in individuals with late onset methylmalonic aciduria and homocystinuria, cblC type (Bodamer 2001, Collison 2015, Lerner-Ellis 2009, Liu 2010, Morel 2006, Rhamander 2014, Tsai 2007, Wang 2012). Functional characterization of the variant protein indicates lower thermostability compared to wild type and impaired binding and stabilization of vitamin B12 (Froese 2010, Gherasim 2015). The variant is listed as pathogenic in ClinVar (Variation ID: 1425), and observed in the general population databases at a frequency of 0.008 percent in the Exome Variant Server (1/12374 alleles), and 0.015 percent in the Genome Aggregation Database (41/277058 alleles). The arginine at residue 161 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 13, 2012 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2016 | - - |
MMACHC-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2023 | The MMACHC c.482G>A variant is predicted to result in the amino acid substitution p.Arg161Gln. This is a commonly reported variant causative for methylmalonic aciduria, cblC type (e.g., Lerner-Ellis et al. 2006. PubMed ID: 16311595; Froese et al. 2009. PubMed ID: 19700356; Hu et al. 2022. PubMed ID: 35361390) and is thought to be associated with a mild and/or late-onset form of cblC type methylmalonic aciduria (Froese et al. 2009. PubMed ID: 19700356; Shi et al. 2015. PubMed ID: 26283149; Almannai et al. 2017. PubMed ID: 28693988). The p.Arg161 amino acid has been highly conserved during evolution, and a different substitution at the same amino acid (p.Arg161Gly) has also been reported to be causative for cblC type methylmalonic aciduria (e.g., Lerner-Ellis et al. 2006. PubMed ID: 16311595). The c.482G>A (p.Arg161Gln) variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. - |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | curation | SingHealth Duke-NUS Institute of Precision Medicine | Jun 07, 2017 | - - |
Methylmalonic acidemia with homocystinuria cblC Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Disorders of Intracellular Cobalamin Metabolism Other:1
not provided, no classification provided | literature only | GeneReviews | - | Associated with milder disease, and may be more common in individuals of Hispanic descent. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at