rs185741664

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020166.5(MCCC1):c.841C>T(p.Arg281*) 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
NM_020166.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.81

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

3-methylcrotonyl-CoA carboxylase 1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
3-methylcrotonyl-CoA carboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

MCCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5 link	c.841C>T	p.Arg281*	stop_gained	Exon 8 of 19	ENST00000265594.9	NP_064551.3	Q96RQ3A0A0S2Z693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 link	c.841C>T	p.Arg281*	stop_gained	Exon 8 of 19	1	NM_020166.5	ENSP00000265594.4		Q96RQ3

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

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

244004

AF XY:

0.0000304

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 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

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.000181

AC:

AN:

44294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1109500

Other (OTH)

AF:

0.00

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000169

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Pathogenic:5

Nov 17, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Mar 02, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MCCC1-related disorder

Pathogenic:1

Sep 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.81

PhyloP100

2.8

Vest4

0.91

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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rs185741664

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over