11-68807553-G-C

Variant names:

• chr11-68807553-G-C
• rs80356775
• NM_001876.4:c.367C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001876.4(CPT1A):​c.367C>G​(p.Arg123Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R123C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.03
• 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, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-68807553-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65653.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	NM_001876.4	MANE Select	c.367C>G	p.Arg123Gly	missense	Exon 4 of 19	NP_001867.2
	CPT1A	NM_001440358.1		c.367C>G	p.Arg123Gly	missense	Exon 4 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.367C>G	p.Arg123Gly	missense	Exon 5 of 20	NP_001427288.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.367C>G	p.Arg123Gly	missense	Exon 4 of 19	ENSP00000265641.4
	CPT1A	ENST00000376618.6	TSL:1	c.367C>G	p.Arg123Gly	missense	Exon 4 of 19	ENSP00000365803.2
	CPT1A	ENST00000540367.5	TSL:1	c.367C>G	p.Arg123Gly	missense	Exon 3 of 18	ENSP00000439084.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.82		Loss of MoRF binding (P = 0.0175)
MVP		0.97
MPC		1.4
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.72
gMVP		0.97
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs80356775; hg19: chr11-68575021;