6-49440295-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.1867G>A(p.Gly623Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G623V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.57

Publications

12 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 21 ACMG points.

PS1

Transcript NM_000255.4 (MMUT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 557096

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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, 0.964

PP5

Variant 6-49440295-C-T is Pathogenic according to our data. Variant chr6-49440295-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1884.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.1867G>A	p.Gly623Arg	missense_variant	Exon 11 of 13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 link	c.1867G>A	p.Gly623Arg	missense_variant	Exon 11 of 13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.1867G>A	p.Gly623Arg	missense_variant	Exon 11 of 13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251316

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111938

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 20, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported to be a common variant in individuals of African descent and functional analysis of G623R found that it is associated with significantly reduced enzyme activity compared to wild-type (Worgan et al., 2006; Janata et al., 1997).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15643616, 7909321, 19375370, 17113806, 31525265, 25087612, 9285782, 8990001, 16281286) -

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 623 of the MUT protein (p.Gly623Arg). This variant is present in population databases (rs121918254, gnomAD 0.008%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 7909321, 15643616, 16281286, 19375370). ClinVar contains an entry for this variant (Variation ID: 1884). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 7909321). For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 17, 2017

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. -

MMUT-related disorder

Pathogenic:1

Aug 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MMUT c.1867G>A variant is predicted to result in the amino acid substitution p.Gly623Arg. This variant has been reported in the homozygous state or heterozygous state with a second MMUT variant in multiple individuals with methylmalonic acidemia (see for example, Qureshi et al. 1994. PubMed ID: 7909321; Worgan et al. 2006. PubMed ID: 16281286; Brassier et al. 2020. PubMed ID: 31525265). In homozygous patients, this variant was associated with a mut0 phenotype (Worgan et al. 2006. PubMed ID: 16281286). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. An in vitro experimental study suggests this variant reduces enzyme activity to 3% of wildtype (Janata et al. 1997. PubMed ID: 9285782). This variant is interpreted as pathogenic. -

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

- -

Methylmalonic acidemia

Pathogenic:1

Jun 13, 2022

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.1867G>A (p.Gly623Arg) 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 251316 control chromosomes. c.1867G>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia supported by characteristic biochemical findings (example, Acquaiva_2005, Worgan_2006, Brassier_2020). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

METHYLMALONIC ACIDURIA, mut(0) TYPE

Pathogenic:1

Apr 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

PhyloP100

7.6

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

1.0

MutPred

0.92

Loss of ubiquitination at K621 (P = 0.0259);

MVP

0.99

MPC

0.53

ClinPred

1.0

GERP RS

5.7

gMVP

0.96

Mutation Taster

=2/98

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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6-49440295-C-T

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