rs150591260

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_022132.5(MCCC2):c.1015G>A(p.Val339Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 4 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26

Conservation

PhyloP100: 9.28

Variant links:

Genes affected

MCCC2 (HGNC:6937): (methylcrotonyl-CoA carboxylase subunit 2) This gene encodes the small subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

MCCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 5-71641018-G-A is Pathogenic according to our data. Variant chr5-71641018-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71641018-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC2	NM_022132.5 link	c.1015G>A	p.Val339Met	missense_variant	Exon 11 of 17	ENST00000340941.11	NP_071415.1	Q9HCC0-1A0A140VK29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11 link	c.1015G>A	p.Val339Met	missense_variant	Exon 11 of 17	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000784

AC:

197

AN:

251374

Hom.:

AF XY:

0.000743

AC XY:

101

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000968

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000676

AC:

988

AN:

1461688

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

509

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000607

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000617

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000675

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000948

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency

Pathogenic:16

Sep 16, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Strong -

Apr 05, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MCCC2 c.1015G>A (p.Val339Met) missense variant has been reported in at least four studies in which it was found in at least seven individuals with 3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency, including in two individuals in a compound heterozygous state and in five individuals in a heterozygous state without a second allele detected (Baumgartner et al. 2001; Wolfe et al. 2007; Grunert et al. 2012; Morscher et al. 2012). The p.Val339Met variant was also found in a compound heterozygous state in nine asymptomatic individuals, eight of whom were identified during newborn screening and presented with biochemical markers associated with 3-MCC deficiency (Grunert et al. 2012; Fonseca et al. 2016). In addition, the variant was also detected in a compound heterozygous state in one individual in whom affected status was unknown and in a heterozygous state in one asymptomatic individual (Grunert et al. 2012; Fonseca et al. 2016). Several of the asymptomatic compound heterozygous individuals carried null alleles on the second allele (Fonseca et al. 2016). The p.Val339Met variant was absent from 200 control chromosomes (Morscher et al. 2012) and is reported at a frequency of 0.00279 in the Other population of the Genome Aggregation Database. The Val339 residue is conserved across species and expression studies in proband fibroblasts found the p.Val339Met variant resulted in 4-12% residual enzyme activity compared to wild type (Baumgartner et al. 2001; Wolfe et al. 2007). Based on the collective evidence, the p.Val399Met variant is classified as likely pathogenic for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously reported in several individuals affected with 3-methylcrotonyl-CoA carboxylase deficiency as compound heterozygous and as heterozygous [PMID: 22642865, 27601257, 11181649, 22642865, 22264772]. Functional studies have shown that the variant is associated with approximately 4% residual enzyme activity compared to wildtype in vitro [PMID: 11181649, 17908719]. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000203805, PMID:11181649). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S, PMID:11181649). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.951>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0008286). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with 3-Methylcrotonyl-CoA carboxylase 2 deficiency (MIM#210210). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 27033733). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 26566957). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methione. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (209 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated CoA carboxyltransferase C-terminal (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar. It has also been reported in both homozygous and compound heterozygous individuals with 3-Methylcrotonyl-CoA carboxylase 2 deficiency (PMID: 34899149, 35281663). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 30, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 10, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 339 of the MCCC2 protein (p.Val339Met). This variant is present in population databases (rs150591260, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency with low MCCC2 enzymatic activity (PMID: 11181649, 22264772, 22642865, 27601257). 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: 203805). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC2 protein function. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 11181649). For these reasons, this variant has been classified as Pathogenic. -

May 02, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MCCC2: PM3:Strong, PM2, PP1, PP3, PP4, PS3:Supporting -

Mar 06, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrated that V339M was associated with approximately 4% residual enzyme activity compared to wildtype (Baumgartner et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25525159, 25087612, 27601257, 16835865, 27033733, 11181649, 27391121, 26990548, 27959697, 22642865, 25356967, 22264772, 17908719, 30510438, 31130284, 34426522, 33238263, 32778825, 33077954) -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MCCC2 c.1015G>A (p.Val339Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251374 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.00078 vs 0.0042), allowing no conclusion about variant significance. c.1015G>A has been reported in the literature in multiple individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30510438, 22642865). Seventeen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Aug 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015G>A (p.V339M) alteration is located in exon 11 (coding exon 11) of the MCCC2 gene. This alteration results from a G to A substitution at nucleotide position 1015, causing the valine (V) at amino acid position 339 to be replaced by a methionine (M). This mutation has been reported in both the homozygous and compound heterozygous state in individuals with 3-methylcrotonyl-CoA carboxylase 2 deficiency (Grünert, 2012; Fonseca, 2016; Posey, 2017; Alsemari, 2018; Monies, 2019). Several were asymptomatic and identified via newborn screening; however, at least two individuals presented with developmental delay or failure to thrive (Fonseca, 2016; Monies, 2019). One patient with a more complex presentation of intellectual disability, short stature, osteopetrosis, calcification of basal ganglia, and thinning of the corpus callosum was homozygous for this mutation as well as variants in three other genes; MCCC2 p.V339M was not thought to explain the patient's phenotype (Alsemari, 2018). In vitro analysis of this mutation demonstrated reduced enzyme activity (4%) compared to wild type (Baumgartner, 2001). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

MCCC2-related disorder

Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MCCC2 c.1015G>A variant is predicted to result in the amino acid substitution p.Val339Met. This variant has been reported in the compound heterozygous state in many patients biochemically and/or enzymatically diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency (e.g., Grünert et al. 2012. PubMed ID: 22642865; Fonseca et al. 2016. PubMed ID: 27601257). This variant has been reported to greatly decrease the activity of the 3-methylcrotonyl-CoA carboxylase enzyme (Baumgartner et al. 2001. PubMed ID: 11181649). It is reported in 0.18% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Based on the collective evidence, this variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Oct 15, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PM3, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

.;H;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.8

.;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.93

MVP

0.99

MPC

0.50

ClinPred

0.27

GERP RS

5.7

Varity_R

0.84

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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