NM_020166.5:c.2123dupA

Variant names:

• chr3-183015492-G-GT
• rs1404350628
• NM_020166.5:c.2123dupA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_020166.5(MCCC1):​c.2123dupA​(p.His708GlnfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCCC1 NM_020166.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.11

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0253 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-183015492-G-GT is Pathogenic according to our data. Variant chr3-183015492-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 654061.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC1	NM_020166.5	c.2123dupA	p.His708GlnfsTer8	frameshift_variant	Exon 19 of 19	ENST00000265594.9	NP_064551.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC1	ENST00000265594.9	c.2123dupA	p.His708GlnfsTer8	frameshift_variant	Exon 19 of 19	1	NM_020166.5	ENSP00000265594.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:1 Uncertain:1

Oct 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has been observed in combination with another MCCC1 variant in an individual affected with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MCCC1 gene (p.His708Glnfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the MCCC1 protein. -

Jan 16, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 13, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MCCC1 c.2123dupA (p.His708GlnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250162 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2123dupA has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (example, Grunert_2012). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, Grunert_2012). The following publication has been ascertained in the context of this evaluation (PMID: 22642865). ClinVar contains an entry for this variant (Variation ID: 654061). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1404350628; hg19: chr3-182733280;