rs769348060

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000255.4(MMUT):c.257C>T(p.Pro86Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,050 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MMUT
NM_000255.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.52

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 6-49459210-G-A is Pathogenic according to our data. Variant chr6-49459210-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553773.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.257C>T	p.Pro86Leu	missense_variant	Exon 2 of 13	ENST00000274813.4	NP_000246.2	P22033A0A024RD82B2R6K1
MMUT	XM_005249143.4 link	c.257C>T	p.Pro86Leu	missense_variant	Exon 2 of 13		XP_005249200.1	P22033A0A024RD82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4 link	c.257C>T	p.Pro86Leu	missense_variant	Exon 2 of 13	1	NM_000255.4	ENSP00000274813.3		P22033

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

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:

0.00

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:

0.0000159

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Pathogenic:2

Mar 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the MUT protein (p.Pro86Leu). This variant is present in population databases (rs769348060, gnomAD 0.01%). This missense change has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 24330302, 27233228). ClinVar contains an entry for this variant (Variation ID: 553773). 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%. For these reasons, this variant has been classified as Pathogenic. -

MMUT-related disorder

Pathogenic:1

Mar 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MMUT c.257C>T variant is predicted to result in the amino acid substitution p.Pro86Leu. This variant has been reported in the compound heterozygous, presumed compound heterozygous, and homozygous states in individuals with methylmalonic acidemia (Worgan et al. 2006. PubMed ID: 16281286; Patient 31, Chu et al. 2016. PubMed ID: 27233228; Nr. 87, Hörster et al. 2020. PubMed ID: 32754920). The c.257C>T variant was also reported in the homozygous state in two unrelated individuals following newborn screening; however, both patients were asymptomatic (Underhill et al. 2013. PubMed ID: 24330302). This variant was also detected in a study of exome sequencing for inborn errors of metabolism in newborns (Supplemental Table 5, Adhikari et al. 2020. PubMed ID: 32778825). Based on in vitro analysis, the c.257C>T (p.Pro86Leu) variant was reported to result in a mild decrease in enzyme activity relative to control, and it was reported to be a thermolabile substitution (Forny et al. 2014. PubMed ID: 25125334). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-49426923-G-A) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/553773/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.93

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-9.2

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.98

MutPred

0.93

Loss of disorder (P = 0.0165);

MVP

1.0

MPC

0.49

ClinPred

1.0

GERP RS

5.6

gMVP

0.92

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