rs150591260

chr5-71641018-G-Achr5-71641018-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V339V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (4 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:22 U:1
• Conservation: PhyloP100: 9.28

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 5-71641018-G-A is Pathogenic according to our data. Variant chr5-71641018-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203805.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=14, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr5-71641018-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC2	NM_022132.5	c.1015G>A	p.Val339Met	missense_variant	11/17	ENST00000340941.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC2	ENST00000340941.11	c.1015G>A	p.Val339Met	missense_variant	11/17	1	NM_022132.5	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152168 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000743 AC XY: 101 AN XY: 135858

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.: 4 Cov.: 30 AF XY: 0.000700 AC XY: 509 AN XY: 727154

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: 94 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74462

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.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:22 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:12 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Jun 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	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). 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) has been performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MCCC2: PM3:Strong, PM2, PP1, PP3, PP4, PS3:Supporting -

Methylcrotonyl-CoA carboxylase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2021

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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 15, 2021

ACMG classification criteria: PS3, PM3, PP3 -

MCCC2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.93
MVP		0.99
MPC		0.50
ClinPred		0.27	T
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

Other links and lift over

dbSNP: rs150591260; hg19: chr5-70936845;