rs201041864

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

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 Likely pathogenic (★★).

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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 2.82

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.

PM1

In a domain ATP-grasp (size 197) in uniprot entity MCCA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_020166.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-183057312-G-A is Pathogenic according to our data. Variant chr3-183057312-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-183057312-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCCC1	NM_020166.5 linkuse as main transcript	c.872C>T	p.Ala291Val	missense_variant, splice_region_variant	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.872C>T	p.Ala291Val	missense_variant, splice_region_variant	8/19	1	NM_020166.5	ENSP00000265594	P1

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

GnomAD3 exomes

AF:

0.000139

AC:

AN:

230448

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

123922

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 SAS exome

AF:

0.0000355

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

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000323

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000180

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000118

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000996

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2023	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; Invitae). 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. -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	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) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2016	- -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 01, 2023

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

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;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

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

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

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