rs121918242

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_015506.3(MMACHC):c.331C>T(p.Arg111*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,030 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

MMACHC
NM_015506.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 2.05

Publications

46 publications found

Variant links:

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]

MMACHC Gene-Disease associations (from GenCC):

methylmalonic aciduria and homocystinuria type cblC
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, ClinGen, G2P, Orphanet

MMACHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-45508266-C-T is Pathogenic according to our data. Variant chr1-45508266-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMACHC	NM_015506.3 link	c.331C>T	p.Arg111*	stop_gained	Exon 3 of 4	ENST00000401061.9	NP_056321.2
MMACHC	NM_001330540.2 link	c.160C>T	p.Arg54*	stop_gained	Exon 3 of 4		NP_001317469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMACHC	ENST00000401061.9 link	c.331C>T	p.Arg111*	stop_gained	Exon 3 of 4	2	NM_015506.3	ENSP00000383840.4
MMACHC	ENST00000616135.1 link	c.160C>T	p.Arg54*	stop_gained	Exon 3 of 5	2		ENSP00000478859.1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000521

AC:

AN:

249450

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111976

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41440

American (AMR)

AF:

0.000196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000627

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cobalamin C disease

Pathogenic:12

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The MMACHC c.331C>T (p.Arg111X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in vitro study showed mRNA leves in cell lines that are homozygotes for c.331C>T showed ~60% decrease compared to wild-type cell lines (Lerner-Ellis_2009), suggesting this nonsense variant leads to nonsense mediated mRNA decay. One in silico tool predicts a damaging outcome for this variant. This variant was found in 9/120818 control chromosomes at a frequency of 0.0000745, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). This variant has been shown to be one of the most common pathogenic variant in CBLC patients and tend to lead to early onset type of disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.

Sep 15, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg111X variant in MMACHC has been reported in at least 29 individuals (9 homozygotes and 20 compound heterozygotes) with methymalonic aciduria and homocy stinuria, cbIC type (Lerner-Ellis 2006). It has been associated with early onset disease (Lerner-Ellis 2006). This variant has been identified in 9/120714 chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs121918242). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. This nonsense variant leads to a premature termination codon at position 1 11, which is predicted to lead to a truncated or absent protein. Loss of functio n of the MMACHC gene is an established disease mechanism for methymalonic acidur ia. In summary, this variant meets our criteria to be classified as pathogenic f or methymalonic aciduria and homocystinuria, cbIC type based upon its co-occurre nce with disease-causing variants in affected individuals, low frequency in cont rol populations, and predicted functional impact.

Nov 02, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 17, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The MMACHC c.331C>T (p.R111*) variant was previously reported in the homozygous or compound heterozygous state in individuals with combined methylmalonic aciduria (also known as methylmalonic acidemia) with homocystinuria (PMID: 16714133; 18164228).

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg111*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs121918242, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria, cblC type (PMID: 16311595, 16714133, 18164228, 24126030). ClinVar contains an entry for this variant (Variation ID: 1424). For these reasons, this variant has been classified as Pathogenic.

MMACHC-related disorder

Pathogenic:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MMACHC c.331C>T variant is predicted to result in premature protein termination (p.Arg111*). This variant has been commonly reported in the literature as causative for methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis et al. 2009, PubMed ID: 19370762; Ricci et al. 2020. PubMed ID: 31503356). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1424). Nonsense variants in MMACHC are expected to be pathogenic. This variant is interpreted as pathogenic.

not provided

Pathogenic:1

Mar 10, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28327205, 30609409, 16311595, 24126030, 28481040, 31503356, 30157807, 31998365, 34215320, 34426522, 32943488, 33473346, 32778825)

Methylmalonic acidemia with homocystinuria cblC

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Disorders of Intracellular Cobalamin Metabolism

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Common in people of Cajun and French Canadian ancestry.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

2.0

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.84

GERP RS

4.8

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over