rs148773718

chr5-71650118-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_022132.5(MCCC2):c.1423G>A(p.Gly475Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.96

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_022132.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 5-71650118-G-A is Pathogenic according to our data. Variant chr5-71650118-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 467803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC2	NM_022132.5	c.1423G>A	p.Gly475Arg	missense_variant	15/17	ENST00000340941.11
MCCC2	NM_001363147.1	c.1309G>A	p.Gly437Arg	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC2	ENST00000340941.11	c.1423G>A	p.Gly475Arg	missense_variant	15/17	1	NM_022132.5	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251378 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000811 AC XY: 59 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	May 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 15, 2017	The MCCC2 c.1423G>A (p.Gly475Arg) missense variant has been reported in two studies and in three individuals with 3-MCC deficiency, including one in a homozygous state and two in a compound heterozygous state (Grünert et al. 2012; Fonseca et al. 2016). The three individuals were asymptomatic and identified by newborn screening. The p.Gly475Arg variant was absent from 100 controls and is reported at a frequency of 0.00079 in the Ashkenazi Jewish population of the Genome Aggregation Database. Expression of wild type and variant p.Gly475Arg in MCCC1/MCCC2 deficient fibroblasts revealed that the variant p.Gly475Arg protein is expressed at a level similar to wild type but has 43.8%-48.5% residual MCC activity compared to wild type (Grünert et al. 2012). Based on the evidence, the p.Gly475Arg 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	Invitae	Nov 17, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 475 of the MCCC2 protein (p.Gly475Arg). This variant is present in population databases (rs148773718, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865, 27601257, 30626930; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 467803). 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 MCCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 22642865). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2022

The c.1423G>A (p.G475R) alteration is located in exon 15 (coding exon 15) of the MCCC2 gene. This alteration results from a G to A substitution at nucleotide position 1423, causing the glycine (G) at amino acid position 475 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (27/282790) total alleles studied. The highest observed frequency was 0.08% (8/10368) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state as well as compound heterozygous with other pathogenic MCCC2 alterations in multiple unrelated individuals with 3-methylcrotonyl-CoA carboxylase deficiency (Grunert, 2012; Fonseca, 2016; Boemer, 2017; Navarrette, 2019; Martin-Rivada, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies showed that p.G475R is not sufficient to rescue MCC deficiency in two different MCC-deficient fibroblast cell lines (Grunert, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 18, 2023

Variant summary: MCCC2 c.1423G>A (p.Gly475Arg) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 9.5e-05 in 251378 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (9.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1423G>A has been reported in the literature in compound heterozygous individuals and at least one homozygous individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Navarrete_2019, Barbosa-Gouveia_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study showed this variant results in decreased MCC activity in transfected cells compared with WT (Grunert_2012). Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

MCCC2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The MCCC2 c.1423G>A variant is predicted to result in the amino acid substitution p.Gly475Arg. This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with MCC deficiency (Grünert et al. 2012. PubMed ID: 22642865; Fonseca et al. 2016. PubMed ID: 27601257; Navarrete et al. 2019. PubMed ID: 30626930; Barbosa-Gouveia et al. 2021. PubMed ID: 34440436). In vitro experimental studies have shown this variant leads to moderately reduced MCC activity (43.8-48.5%) relative to WT (Grünert et al. 2012. PubMed ID: 22642865). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2022

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: 22642865, 27601257, 30626930, 32778825, 35281663, 34440436) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.88		Gain of MoRF binding (P = 0.0215);.;
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

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

Other links and lift over

dbSNP: rs148773718; hg19: chr5-70945945;