1-53210354-C-T

Position:

chr1-53210354-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000098.3(CPT2):c.680C>T(p.Pro227Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,108 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CPT2
NM_000098.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

CPT2 (HGNC:2330): (carnitine palmitoyltransferase 2) The protein encoded by this gene is a nuclear protein which is transported to the mitochondrial inner membrane. Together with carnitine palmitoyltransferase I, the encoded protein oxidizes long-chain fatty acids in the mitochondria. Defects in this gene are associated with mitochondrial long-chain fatty-acid (LCFA) oxidation disorders. [provided by RefSeq, Jul 2008]

CPT2 links:

ENSG00000236723 (HGNC:):

ENSG00000236723 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 1-53210354-C-T is Pathogenic according to our data. Variant chr1-53210354-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3 link	c.680C>T	p.Pro227Leu	missense_variant	4/5	ENST00000371486.4	NP_000089.1	P23786A0A140VK13
CPT2	NM_001330589.2 link	c.680C>T	p.Pro227Leu	missense_variant	4/5		NP_001317518.1	A0A1B0GTB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4 link	c.680C>T	p.Pro227Leu	missense_variant	4/5	1	NM_000098.3	ENSP00000360541.3		P23786

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250730

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.000803

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000315

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000748

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21709843, 10090476, 18550408, 25827434, 9758712, 22975760, 12673791) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 26, 2021	PP3, PP4, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	The CPT2 c.680C>T p.Pro227Leu variant (rs74315298) is reported as homozygous or compound heterozygous in the literature in multiple individuals with CPT II deficiency (Boemer 2016, Hissink-Muller 2009, Isackson 2008, Yang 1998). This variant is reported in ClinVar (Variation ID: 8964) and is found in the African population with an allele frequency of 0.1% (25/24906 alleles) in the Genome Aggregation Database. The proline at codon 227 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.985). Based on available information, this variant is considered to be pathogenic. References: Boemer F et al. Diagnostic pitfall in antenatal manifestations of CPT II deficiency. Clin Genet. 2016 Feb;89(2):193-7. PMID: 25827434. Hissink-Muller P et al. Neonatal carnitine palmitoyltransferase II deficiency: failure of treatment despite prolonged survival. BMJ Case Rep. 2009;2009:bcr02.2009.1550.PMID: 21709843; PMCID: PMC3027782. Isackson PJ et a. CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. Mol Genet Metab. 2008 Aug;94(4):422-427. PMID: 18550408. Yang BZ et al. Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency. Mol Genet Metab. 1998 Aug;64(4):229-36. PMID: 9758712. -

Carnitine palmitoyltransferase II deficiency

Pathogenic:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2023	Variant summary: CPT2 c.680C>T (p.Pro227Leu) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250730 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency (5.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.680C>T has been reported in the literature in multiple individuals affected with Carnitine Palmitoyltransferase II Deficiency (example: Boemer_2016 and Hissink-Muller_2009). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2025	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 227 of the CPT2 protein (p.Pro227Leu). This variant is present in population databases (rs74315298, gnomAD 0.1%). This missense change has been observed in individual(s) with carnitine palmitoyltransferase II deficiency (PMID: 9758712, 18550408, 21709843, 25827434). ClinVar contains an entry for this variant (Variation ID: 8964). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CPT2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Carnitine palmitoyl transferase II deficiency, neonatal form

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 31, 2024	- -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 22, 2022	ACMG classification criteria: PM2 supporting, PM3 strong, PP3 supporting -

Carnitine palmitoyl transferase II deficiency, myopathic form;C1833511:Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form;C3280160:Encephalopathy, acute, infection-induced, susceptibility to, 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 13, 2024

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

CPT2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The CPT2 c.680C>T variant is predicted to result in the amino acid substitution p.Pro227Leu. This variant has been reported, in the homozygous state or heterozygous state with a second CPT2 variant, in several patients with the neonatal form of carnitine palmitoyltransferase (CPT) II deficiency (Yang et al. 1998. PubMed ID: 9758712; Isackson et al. 2008. PubMed ID: 18550408; Hissink-Muller et al. 2009. PubMed ID: 21709843; Boemer et al. 2016. PubMed ID: 25827434). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic for recessive disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-9.2

D;.;.;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MVP

1.0

MPC

0.56

ClinPred

1.0

GERP RS

5.5

Varity_R

0.95

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over