3-183057343-G-A

Position:

chr3-183057343-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000265594.9(MCCC1):c.841C>T(p.Arg281Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,609,548 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MCCC1
ENST00000265594.9 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.81

Variant links:

Genes affected

MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large 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. [provided by RefSeq, Jul 2008]

MCCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-183057343-G-A is Pathogenic according to our data. Variant chr3-183057343-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-183057343-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC1	NM_020166.5 linkuse as main transcript	c.841C>T	p.Arg281Ter	stop_gained	8/19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 linkuse as main transcript	c.841C>T	p.Arg281Ter	stop_gained	8/19	1	NM_020166.5	ENSP00000265594	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000451

AC:

AN:

244004

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000206

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:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1457340

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

724468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000181

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Arg281*) in the MCCC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCCC1 are known to be pathogenic (PMID: 11181649, 15359379, 22642865). This variant is present in population databases (rs185741664, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mild biochemical features of 3MCC deficiency (PMID: 22264772, 22642865). ClinVar contains an entry for this variant (Variation ID: 203795). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 12, 2021	- -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 02, 2016

- -

MCCC1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2023

The MCCC1 c.841C>T variant is predicted to result in premature protein termination (p.Arg281*). This variant has been documented in one patient diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency and presenting with developmental delay. This patient carried the c.841C>T in the heterozygous state and no second variant was found (Morscher et al. 2012, PMID 22264772). This variant is reported in 0.021% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-182775131-G-A). Nonsense variants in MCCC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.81

MutationTaster

Benign

1.0

A;A;A

Vest4

0.91

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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