rs1594313040

Variant names:

• chr11-68757704-C-CAGG
• rs1594313040
• NM_001876.4:c.2259_2261dupCCT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_001876.4(CPT1A):​c.2259_2261dupCCT​(p.Leu754dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L754L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

Genes affected

CPT1A (HGNC:2328): (carnitine palmitoyltransferase 1A) The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CPT1A Gene-Disease associations (from GenCC):

• carnitine palmitoyl transferase 1A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001876.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-68757704-C-CAGG is Pathogenic according to our data. Variant chr11-68757704-C-CAGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 802697.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	NM_001876.4	MANE Select	c.2259_2261dupCCT	p.Leu754dup	disruptive_inframe_insertion	Exon 19 of 19	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.2259_2261dupCCT	p.Leu754dup	disruptive_inframe_insertion	Exon 19 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.2259_2261dupCCT	p.Leu754dup	disruptive_inframe_insertion	Exon 20 of 20	NP_001427288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.2259_2261dupCCT	p.Leu754dup	disruptive_inframe_insertion	Exon 19 of 19	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.2235+1862_2235+1864dupCCT		intron	N/A	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.2235+1862_2235+1864dupCCT		intron	N/A	ENSP00000439084.1	P50416-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Carnitine palmitoyl transferase 1A deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

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

Other links and lift over

dbSNP: rs1594313040; hg19: chr11-68525172;