rs201041864

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP5

The NM_020166.5(MCCC1):c.872C>T(p.Ala291Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,598,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A291E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

MCCC1
NM_020166.5 missense, splice_region

Scores

Splicing: ADA: 0.001581

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 2.82

Publications

7 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_020166.5

PP5

Variant 3-183057312-G-A is Pathogenic according to our data. Variant chr3-183057312-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476401.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5 link	c.872C>T	p.Ala291Val	missense_variant, splice_region_variant	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.872C>T	p.Ala291Val	missense_variant, splice_region_variant	Exon 8 of 19	1	NM_020166.5	ENSP00000265594.4		Q96RQ3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

230448

AF XY:

0.000129

show subpopulations

Gnomad AFR exome

AF:

0.0000681

Gnomad AMR exome

AF:

0.000334

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000158

AC:

229

AN:

1446376

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

718098

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33264

American (AMR)

AF:

0.000323

AC:

AN:

43338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25776

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.0000238

AC:

AN:

83972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000180

AC:

198

AN:

1102210

Other (OTH)

AF:

0.000234

AC:

AN:

59772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.000262

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Pathogenic:3

Mar 29, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 291 of the MCCC1 protein (p.Ala291Val). This variant is present in population databases (rs201041864, gnomAD 0.03%). This missense change has been observed in individuals with biochemical testing consistent with 3-MCC deficiency (PMID: 16010683, 22642865, 30626930; internal data). ClinVar contains an entry for this variant (Variation ID: 476401). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 16010683). For these reasons, this variant has been classified as Pathogenic. -

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Jul 24, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Expression studies found that this variant is associated with significantly reduced MCC activity compared to wild-type (Dantas MF et al., 2005); 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: 30626930, 35281663, 31737040, 16010683, 31730530, 22642865) -

Nov 30, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

Nov 01, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MCCC1 c.872C>T (p.Ala291Val) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 230448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC1 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.00014 vs 0.0042), allowing no conclusion about variant significance. c.872C>T has been reported in the literature in multiple individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (Dantas_2005, Shepard_2015, Wang_2019, Navarrete_2019, Martn-Rivada_2022). These data indicate that the variant is likely to be associated with disease. The variant was examined via transfection assays using MCCC1 deficient cells, and the variant was found with 26% enzymatic activity compared to wild-type (Dantas_2005). The following publications have been ascertained in the context of this evaluation (PMID: 25356967, 30626930, 16010683, 31730530, 35281663). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

D;D;D;D;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.72

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

D;D;.;.;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.015

D;D;.;.;D

Sift4G

Uncertain

0.029

D;D;D;D;.

Polyphen

0.98

D;B;.;.;D

Vest4

0.77

MVP

0.97

MPC

0.59

ClinPred

0.90

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.87

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.26

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over