chr3-183022453-CAGCTTCGCTTTACT-C

Variant names:

• chr3-183022453-CAGCTTCGCTTTACT-C
• rs1553850609
• NM_020166.5:c.1819_1832delAGTAAAGCGAAGCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_020166.5(MCCC1):​c.1819_1832delAGTAAAGCGAAGCT​(p.Ser607AspfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCCC1 NM_020166.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.02
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-183022453-CAGCTTCGCTTTACT-C is Pathogenic according to our data. Variant chr3-183022453-CAGCTTCGCTTTACT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 476396.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020166.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	NM_020166.5	MANE Select	c.1819_1832delAGTAAAGCGAAGCT	p.Ser607AspfsTer17	frameshift	Exon 16 of 19	NP_064551.3
	MCCC1	NM_001363880.1		c.1492_1505delAGTAAAGCGAAGCT	p.Ser498AspfsTer17	frameshift	Exon 15 of 18	NP_001350809.1
	MCCC1	NM_001293273.2		c.1468_1481delAGTAAAGCGAAGCT	p.Ser490AspfsTer17	frameshift	Exon 14 of 17	NP_001280202.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC1	ENST00000265594.9	TSL:1 MANE Select	c.1819_1832delAGTAAAGCGAAGCT	p.Ser607AspfsTer17	frameshift	Exon 16 of 19	ENSP00000265594.4
	MCCC1	ENST00000492597.5	TSL:1	c.1492_1505delAGTAAAGCGAAGCT	p.Ser498AspfsTer17	frameshift	Exon 15 of 18	ENSP00000419898.1
	MCCC1	ENST00000497830.5	TSL:1	n.*1416_*1429delAGTAAAGCGAAGCT		non_coding_transcript_exon	Exon 14 of 17	ENSP00000420088.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:1

Dec 30, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in MCCC1 are known to be pathogenic (PMID: 16010683). This sequence change deletes 14 nucleotides from exon 16 of the MCCC1 mRNA (c.1819_1832delAGTAAAGCGAAGCT), causing a frameshift at codon 607. This creates a premature translational stop signal (p.Ser607Aspfs*17) and is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553850609; hg19: chr3-182740241;