NM_000255.4:c.2206C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_000255.4(MMUT):​c.2206C>T​(p.Leu736Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,826 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

4
12
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 2.54

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
  • vitamin B12-unresponsive methylmalonic acidemia type mut-
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • vitamin B12-unresponsive methylmalonic acidemia type mut0
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a domain B12-binding (size 132) in uniprot entity MUTA_HUMAN there are 42 pathogenic changes around while only 3 benign (93%) in NM_000255.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 150 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.22855 (below the threshold of 3.09). Trascript score misZ: 1.0842 (below the threshold of 3.09). GenCC associations: The gene is linked to vitamin B12-unresponsive methylmalonic acidemia type mut-, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut0.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
PP5
Variant 6-49431775-G-A is Pathogenic according to our data. Variant chr6-49431775-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555168.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MMUTNM_000255.4 linkc.2206C>T p.Leu736Phe missense_variant Exon 13 of 13 ENST00000274813.4 NP_000246.2 P22033A0A024RD82B2R6K1
MMUTXM_005249143.4 linkc.2206C>T p.Leu736Phe missense_variant Exon 13 of 13 XP_005249200.1 P22033A0A024RD82

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MMUTENST00000274813.4 linkc.2206C>T p.Leu736Phe missense_variant Exon 13 of 13 1 NM_000255.4 ENSP00000274813.3 P22033

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251402
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461724
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39676
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000719
AC:
8
AN:
1111898
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.403
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74280
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1Uncertain:2
Nov 21, 2017
Counsyl
Significance:Uncertain significance
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. -

Oct 17, 2023
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 17, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins Pathogenic:1
Mar 06, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: MMUT c.2206C>T (p.Leu736Phe) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain (IPR006158) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes. c.2206C>T has been reported in the literature in individuals affected with methylmalonic aciduria who were reported as compound heterozygous with other pathogenic variants (Forny_2014, Martin-Rivada_2022, Yu_2021). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, resulting in 13% of normal activity (Forny_2014). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1
Oct 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 736 of the MUT protein (p.Leu736Phe). This variant is present in population databases (rs753461919, gnomAD 0.003%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 27167370, 34668645, 35281663, 36717752). ClinVar contains an entry for this variant (Variation ID: 555168). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.71
D
PhyloP100
2.5
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0090
D
Vest4
0.74
MutPred
0.39
Loss of ubiquitination at K741 (P = 0.198);
MVP
0.98
MPC
0.41
ClinPred
0.96
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.81
Mutation Taster
=19/81
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs753461919; hg19: chr6-49399488; API