5-71641068-A-T

Position:

chr5-71641068-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_022132.5(MCCC2):c.1065A>T(p.Leu355Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,613,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 1.86

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:

MCCC2 (HGNC:):

MCCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-71641068-A-T is Pathogenic according to our data. Variant chr5-71641068-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC2	NM_022132.5 linkuse as main transcript	c.1065A>T	p.Leu355Phe	missense_variant	11/17	ENST00000340941.11	NP_071415.1	Q9HCC0-1A0A140VK29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11 linkuse as main transcript	c.1065A>T	p.Leu355Phe	missense_variant	11/17	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000358

AC:

AN:

251280

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1461014

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000105

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2024	The p.Leu355Phe variant in MCCC2 has been reported in the homozygous state in at least 9 individuals and in the compound heterozygote state with another pathogenic variant in MCCC2 in 2 individuals with 3-methylcrotonyl-CoA (MCC) deficiency or a positive newborn screen (Nguyen 2011 PMID: 21071250, Shepard 2015 PMID: 25356967, Forsyth 2016 PMID: 27033733, GeneDx pers. comm., Invitae pers. comm.). Most of these individuals were typically asymptomatic at the time of testing, however had MCC deficiency determined by biochemical analyses. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 203806) and has been identified in 0.085% (13/15282) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MCC deficiency. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PP4. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2021	Variant summary: MCCC2 c.1065A>T (p.Leu355Phe) 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 0.00036 in 251280 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.00036 vs 0.0042), allowing no conclusion about variant significance. c.1065A>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency with characteristic biochemical profiles, namely, elevated excretion of 3-hydroxyisovaleric acid (3-HIVA), 3-methylcrotonylglycine (3-MCG) and also subsequently cited by others (example, Nguyen_2011, Grunert_2012, Adhikari_2020, Shepard_2015, Fonseca_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%-<30% of normal MCC enzyme activity in a homozygous individual. Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

3-methylcrotonyl-CoA carboxylase 2 deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 355 of the MCCC2 protein (p.Leu355Phe). This variant is present in population databases (rs757052602, gnomAD 0.3%). This missense change has been observed in individual(s) with 3-methylcrotonylglycinuria (PMID: 21071250, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 203806). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 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: 25356967, 22642865, 27033733, 21071250) -

MCCC2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

The MCCC2 c.1065A>T variant is predicted to result in the amino acid substitution p.Leu355Phe. This variant has been reported in the homozygous state in multiple apparently unrelated individuals with enzymatically confirmed 3-methylcrotonyl-CoA carboxylase deficiency, though it should be noted that two of these patients were asymptomatic adults (Nguyen et al. 2011. PubMed ID: 21071250; Shepard et al. 2015. PubMed ID: 25356967). It has also been reported in the heterozygous state with a second heterozygous likely pathogenic MCCC2 variant in a patient who was reportedly clinically “normal” during the neonatal period (Forsyth et al. 2016. PubMed ID: 27033733). This variant is reported in 0.26% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic or pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203806). Taken together, this variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Jul 20, 2021

Nguyen, 2011; Shepard, 2015; Forsyth, 2016 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

.;H;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.8

.;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.84

MutPred

0.73

.;Loss of stability (P = 0.111);Loss of stability (P = 0.111);

MVP

0.99

MPC

0.53

ClinPred

0.93

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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