NM_000255.4:c.2179C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000255.4(MMUT):c.2179C>T(p.Arg727*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000018 in 1,613,668 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MMUT
NM_000255.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 4.57

Variant links:

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MMUT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0328 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-49431802-G-A is Pathogenic according to our data. Variant chr6-49431802-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218998.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
MMUT	NM_000255.4 link	c.2179C>T	p.Arg727*	stop_gained	Exon 13 of 13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 link	c.2179C>T	p.Arg727*	stop_gained	Exon 13 of 13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.2179C>T	p.Arg727*	stop_gained	Exon 13 of 13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251350

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000456

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

mut(0) enzymatic subtype when homozygous -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000218998 / PMID: 16281286). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 25, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 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.Arg727*) in the MUT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the MUT protein. This variant is present in population databases (rs779990936, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 16281286, 17075691, 17445044, 22727635, 26454439, 27489777). 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: 218998). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic acidemia

Pathogenic:2

Aug 15, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUT c.2179C>T (p.Arg727X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251350 control chromosomes (gnomAD). c.2179C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Sakamoto_2007, Chu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg727X variant in MMUT has been reported, in the homozygous or compound heterozygous state, in several individuals affected with methylmalonic acidemia (Worgan 2006 PMID: 16281286, Oyama 2007 PMID: 17445044, Chu 2016 PMID: 27233228, Dündar 2012 PMID 22727635, Sakamoto 2007 PMID: 17075691, Han 2015 PMID: 26454439,Burlina 2016 PMID: 27489777). It has also been reported in ClinVar (Variation ID 218998) and it has been identified in 2/68004 European chromosomes by gnomADv. 3 (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination: codon at position 727. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic acidemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_VeryStrong. -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Abnormality of metabolism/homeostasis

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

Vest4

0.85

GERP RS

4.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over