rs119103213

Positions:

chr3-183041679-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_020166.5(MCCC1):c.1155A>C(p.Arg385Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,088 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 (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -0.198

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 3-183041679-T-G is Pathogenic according to our data. Variant chr3-183041679-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1930.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
MCCC1	NM_020166.5 link	c.1155A>C	p.Arg385Ser	missense_variant	11/19	ENST00000265594.9	NP_064551.3	Q96RQ3A0A0S2Z693

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9 link	c.1155A>C	p.Arg385Ser	missense_variant	11/19	1	NM_020166.5	ENSP00000265594.4		Q96RQ3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251452

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 385 of the MCCC1 protein (p.Arg385Ser). This variant is present in population databases (rs119103213, gnomAD 0.03%). This missense change has been observed in individuals with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 16835865, 22642865, 25356967). ClinVar contains an entry for this variant (Variation ID: 1930). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MCCC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 14680978, 15359379, 15868465). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2018	Across a selection of literature the MCCC1 c.1155A>C (p.Arg385Ser) missense variant has been reported in at least 14 individuals with 3-MCC deficiency that were both symptomatic and asymptomatic. The variant was found in a homozygous state in three subjects and in a compound heterozygous state in 11 subjects (Gallardo et al. 2001; Baumgartner et al. 2001; Baumgartner et al. 2004; Dantas et al. 2005; Stadler et al. 2006; Morscher et al. 2012; Grunert et al. 2012; Shepard et al. 2015). The p.Arg385Ser variant was found in one of 216 control individuals and is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Exome Aggregation Consortium. In cultured skin fibroblasts from patients carrying the p.Arg385Ser variant, MCC activity was typically less than 10% of normal (Gallardo et al. 2001; Baumgartner et al. 2001; Stadler et al. 2006). Baumgartner et al. (2001) demonstrated that the p.Arg385Ser variant conferred no detectable MCC activity when expressed in a reference cell line, though normal amounts of the protein were detected, and Baumgartner et al. (2004) showed that the MCC activity was reduced when the p.Arg385Ser variant was co-transfected with the wild type allele, which indicated a dominant negative effect. Based on the evidence the p.Arg385Ser variant is classified as pathogenic for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2021	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2025	Published functional studies found this variant is associated with significantly reduced MCC activity (PMID: 15359379, 14960587); 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: 14960587, 31980526, 34426522, 31589614, 14680978, 27601257, 25356967, 22642865, 16010683, 11170888, 16773504, 15359379) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MCCC1: PM3:Strong, PM1, PM2, PM5:Supporting, PS3:Supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2021

The c.1155A>C (p.R385S) alteration is located in exon 11 (coding exon 11) of the MCCC1 gene. This alteration results from an A to C substitution at nucleotide position 1155, causing the arginine (R) at amino acid position 385 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (37/282844) total alleles studied. The highest observed frequency was 0.03% (35/129160) of European (non-Finnish) alleles. This alteration has been detected as compound heterozygous and homozygous in multiple unrelated individuals with MCC deficiency confirmed by biochemical analyses (Baumgartner, 2001; Gallardo, 2001; Baumgartner, 2004; Grünert, 2012; Smon, 2018). Multiple studies show that this alteration resulted in no detectable MCC activity and failed to restore MCC activity in MCCC1-deficient fibroblasts (Baumgartner, 2001; Desviat, 2003; Baumgartner, 2004). Based on the available evidence, this alteration is classified as pathogenic. -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D;D;D;D

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.8

D;D;.;.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;.;.;D

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

1.0

D;D;.;.;D

Vest4

0.99

MutPred

0.94

Gain of glycosylation at R385 (P = 0.0332);.;.;.;.;

MVP

0.98

MPC

0.62

ClinPred

0.98

GERP RS

0.44

Varity_R

0.99

gMVP

0.96

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

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