chr6-49453754-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.914T>C(p.Leu305Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L305F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.95

Publications

5 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

MMUT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000255.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-49453753-C-A is described in CliVar as Likely_pathogenic. Clinvar id is 3393130.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.989

PP5

Variant 6-49453754-A-G is Pathogenic according to our data. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49453754-A-G is described in CliVar as Pathogenic. Clinvar id is 556865.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.914T>C	p.Leu305Ser	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 link	c.914T>C	p.Leu305Ser	missense_variant, splice_region_variant	Exon 5 of 13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.914T>C	p.Leu305Ser	missense_variant, splice_region_variant	Exon 5 of 13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39512

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110080

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Feb 09, 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 serine, which is neutral and polar, at codon 305 of the MUT protein (p.Leu305Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with methylmalonic academia (PMID: 16281286, 22727635, 27167370, 29896740). 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: 556865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:1

Feb 21, 2018

Counsyl

Significance:Likely 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. -

Methylmalonic acidemia

Pathogenic:1

Apr 26, 2024

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.914T>C (p.Leu305Ser) results in a non-conservative amino acid change located in the methylmalonyl-CoA mutase, alpha chain, catalytic domain (IPR006098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. The variant was absent in 250700 control chromosomes. c.914T>C has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia in the compound heterozygous and homozygous states (e.g. Dundar_2012, Kang_2020, Worgan_2006, Forny_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22727635, 27167370, 31622506, 16281286). ClinVar contains an entry for this variant (Variation ID: 556865). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.98

PhyloP100

8.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.98

MutPred

0.95

Loss of stability (P = 0.0124);

MVP

1.0

MPC

0.57

ClinPred

1.0

GERP RS

5.3

gMVP

0.98

Mutation Taster

=23/77

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