rs121918243

chr1-45508848-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_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:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MMACHC NM_015506.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 9.36

Genes affected

MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_015506.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45508847-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 1-45508848-G-A is Pathogenic according to our data. Variant chr1-45508848-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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: 11 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 43 AN: 249432 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135328

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727234

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cobalamin C disease Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
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, 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	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, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 24, 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	Eurofins Ntd Llc (ga)	Jul 13, 2012	- -
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. -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MVP		0.98
MPC		0.067
ClinPred		0.76	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918243; hg19: chr1-45974520; COSMIC: COSV105011592; COSMIC: COSV105011592;