rs121918257

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000255.4(MMUT):c.322C>T(p.Arg108Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 4.71

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 16 ACMG points.

PM1

In a strand (size 5) in uniprot entity MUTA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 6-49459145-G-A is Pathogenic according to our data. Variant chr6-49459145-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49459145-G-A is described in Lovd as [Pathogenic]. Variant chr6-49459145-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4 linkuse as main transcript	c.322C>T	p.Arg108Cys	missense_variant	2/13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 linkuse as main transcript	c.322C>T	p.Arg108Cys	missense_variant	2/13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 linkuse as main transcript	c.322C>T	p.Arg108Cys	missense_variant	2/13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251326

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS 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:

0.0000233

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16281286, 30564975, 24464670, 31622506, 31998365, 31525265, 31466887, 27578510, 29330964, 26454439) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 108 of the MUT protein (p.Arg108Cys). This variant is present in population databases (rs121918257, gnomAD 0.08%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 2661559, 16281286, 17075691, 22614770, 23045948, 24059531, 24464670, 27578510). 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: 1887). 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%. This variant disrupts the p.Arg108 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 17113806, 22614770, 23430940, 25750861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Methylmalonic acidemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a compound heterozygous and homozygous change in patients with methylmalonic acidemia (PMID: 16281286, 17075691, 24059531, 23045948, 2661559, 22614770, 24464670, 27578510). The c.322C>T (p.Arg108Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.012% (30/251326), and is absent in the homozygous state; thus it is presumed to be rare. The c.322C>T (p.Arg108Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.322C>T (p.Arg108Cys) variant is classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2019	Variant summary: MUT c.322C>T (p.Arg108Cys) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain 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 0.00011 in 246146 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as measured by decreased incorporation of label from carbon-14 labeled propionate into cellular macromolecules (Worgan_2006). Three 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

METHYLMALONIC ACIDURIA, mut(0) TYPE

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 06, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	mut(0) enzymatic subtype when homozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The c.322C>T (p.R108C) alteration is located in exon 2 (coding exon 1) of the MUT gene. This alteration results from a C to T substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (30/251326) total alleles studied. The highest observed frequency was 0.08% (29/34552) of Latino alleles. This mutation has been reported in the homozygous and compound heterozygous state in several individuals with MUT-related methylmalonic aciduria (Worgan, 2006; Zhang, 2019; Han, 2020). Another alteration at the same codon, p.R108H (c.323G>A), has been detected in individuals with MUT-related methylmalonic aciduria in conjunction with a second MUT alteration (Worgan, 2006; Lempp, 2007). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

MMUT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2024

The MMUT c.322C>T variant is predicted to result in the amino acid substitution p.Arg108Cys. This variant has been documented as a recurrent variant causative for methylmalonic acidemia, in both the homozygous and compound heterozygous state (e.g., Worgan et al. 2006. PubMed ID: 16281286; Park et al. 2016. PubMed ID: 27578510; Zhang et al. 2019. PubMed ID: 31998365; Brassier et al. 2020. PubMed ID: 31525265; Han et al. 2020. PubMed ID: 31466887). In the homozygous state, it has been reported as a mut0 variant; it is particularly common in individuals of Hispanic descent (Worgan et al. 2006. PubMed ID: 16281286). Based on these observations and the data in the above table, we classify this variant as pathogenic. -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.97

MVP

0.99

MPC

0.57

ClinPred

0.99

GERP RS

5.6

gMVP

0.95

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