rs74315298

chr1-53210354-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.57

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]

(HGNC:):

ACMG classification

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	UniProt
CPT2	NM_000098.3	c.680C>T	p.Pro227Leu	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.680C>T	p.Pro227Leu	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.680C>T	p.Pro227Leu	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.341G>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152150 Hom.: 0 Cov.: 32

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: 13 AN: 250730 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135604

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: 36 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727222

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: 48 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74446

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.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	Mayo Clinic Laboratories, Mayo Clinic	Nov 26, 2021	PP3, PP4, PM3, PS3, PS4_moderate -
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	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:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 19, 2020	- -
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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPT2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:3

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 -
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	- -

Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -

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 09, 2022

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

CPT2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	26
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	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.54	T
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	D
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

Other links and lift over

dbSNP: rs74315298; hg19: chr1-53676026;