rs905321122

chr3-183020177-C-Achr3-183020177-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020166.5(MCCC1):c.1930G>T(p.Glu644Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,614,026 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MCCC1 NM_020166.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.38

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]

ACMG classification

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 3-183020177-C-A is Pathogenic according to our data. Variant chr3-183020177-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 503626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC1	NM_020166.5	c.1930G>T	p.Glu644Ter	stop_gained	17/19	ENST00000265594.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC1	ENST00000265594.9	c.1930G>T	p.Glu644Ter	stop_gained	17/19	1	NM_020166.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 33

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Glu644*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865). ClinVar contains an entry for this variant (Variation ID: 503626). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2017

The E644X nonsense variant in the MCCC1 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Dantas et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense mediated mRNA decay. The E644X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, we interpret E644X to be a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.60	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.77
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs905321122; hg19: chr3-182737965;