Variant rs111033538 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_032601.4(MCEE):c.139C>T(p.Arg47*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000444 in 1,613,948 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 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

MCEE
NM_032601.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 4.53

Variant links:

Genes affected

MCEE (HGNC:16732): (methylmalonyl-CoA epimerase) The product of this gene catalyzes the interconversion of D- and L-methylmalonyl-CoA during the degradation of branched chain amino acids. odd chain-length fatty acids, and other metabolites. Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MCEE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-71124445-G-A is Pathogenic according to our data. Variant chr2-71124445-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCEE	NM_032601.4 linkuse as main transcript	c.139C>T	p.Arg47*	stop_gained	2/3	ENST00000244217.6	NP_115990.3	Q96PE7
MCEE	XM_047446039.1 linkuse as main transcript	c.139C>T	p.Arg47*	stop_gained	2/3		XP_047301995.1
MCEE	XM_005264613.3 linkuse as main transcript	c.139C>T	p.Arg47*	stop_gained	2/3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCEE	ENST00000244217.6 linkuse as main transcript	c.139C>T	p.Arg47*	stop_gained	2/3	1	NM_032601.4	ENSP00000244217.5		Q96PE7

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251162

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000460

AC:

673

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000568

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000289

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000504

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000830

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Arg47*) in the MCEE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCEE are known to be pathogenic (PMID: 16697227, 16752391, 30682498). This variant is present in population databases (rs111033538, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with methylmalonyl-CoA epimerase deficiency (PMID: 16752391, 27699154, 29104221). ClinVar contains an entry for this variant (Variation ID: 2343). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 19, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 12, 2018	The MCEE c.139C>T (p.Arg47Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. It has been reported in eight patients with methylmalonic acidemia (Bikker et al. 2006; Dobson et al. 2006; Gradinger et al. 2007; Mazzuca et al. 2015; Waters et al. 2016; Abily-Donval et al. 2017). Within this group, which included two sibling pairs, seven individuals were homozygous; the remaining patient was compound heterozygous for p.Arg47Ter and an intron variant that induced aberrant splicing. The phenotypic presentation of these patients was variable, ranging from the absence of clinical symptoms to language, motor, and neurological impairment. In two unrelated patients with a more severe phenotype, the methylmalonyl-CoA epimerase deficiency was combined with sepiapterin reductase deficiency. In at least one homozygous patient, inheritance of the variant from healthy carrier parents was demonstrated. The p.Arg47Ter variant was absent from 197 control individuals and is reported at a frequency of 0.000698 in the European American population of the Exome Sequencing Project. Fibroblasts from homozygous patients were complemented by mut, cblA, and cblB fibroblasts and infection with wild type MCEE cDNA corrected the biochemical phenotype, consistent with decreased [14C]propionate incorporation due to reduced epimerase function (Gradinger et al. 2007). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg47Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MCEE: PM3:Strong, PP1:Strong, PM2, PVS1:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	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; This variant is associated with the following publications: (PMID: 25525159, 16752391, 27699154, 16697227, 17823972, 31146325, 34426522, 31589614, 36305448, 38034150, 31345219, 33726816, 31980526, 29104221, 30682498) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.139C>T (p.R47*) alteration, located in exon 2 (coding exon 2) of the MCEE gene, consists of a C to T substitution at nucleotide position 139. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 47. The predicted stop codon occurs in the 5' end of the MCEE gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. The c.139C>T (p.R47*) alteration has been reported in multiple individuals diagnosed with methylmalonyl-CoA epimerase deficiency in both the homozygous and compound heterozygous states (Abily-Donval, 2017; Andréasson, 2019; Bikker, 2006; Dobson, 2006; Gradinger, 2007; Heuberger, 2019; Waters, 2016). In vitro findings in cultured fibroblasts showed a decrease in propionate incorporation into macromolecules and normal activity of methylmalonyl-CoA mutase (Bikker, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

MCEE-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

The MCEE c.139C>T variant is predicted to result in premature protein termination (p.Arg47*). This variant was reported in the homozygous state or with a second MCEE variant in patients with methylmalonic aciduria (Bikker et al. 2006. PubMed ID: 16752391; Waters et al. 2016. PubMed ID: 27699154; Abily-Donval et al. 2017. PubMed ID: 29104221; Heuberger et al. 2019. PubMed ID: 30682498). This variant is reported in 0.049% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Methylmalonic acidemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 13, 2023

Variant summary: MCEE c.139C>T (p.Arg47X) results in a premature termination codon and is expected to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00026 in 251162 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MCEE causing Methylmalonic Acidemia (0.00026 vs 0.0005), allowing no conclusion about variant significance. c.139C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (e.g. Heuberger_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30682498). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

Vest4

0.20

GERP RS

3.5

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