NM_000098.3(CPT2):c.1511C>T (p.Pro504Leu) AND Carnitine palmitoyltransferase II deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000778986.13

Allele description

NM_000098.3(CPT2):c.1511C>T (p.Pro504Leu)

Gene:

CPT2:carnitine palmitoyltransferase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_000098.3(CPT2):c.1511C>T (p.Pro504Leu)

HGVS:

NC_000001.11:g.53211185C>T
NG_008035.1:g.19757C>T
NM_000098.3:c.1511C>TMANE SELECT
NM_001330589.2:c.1511C>T
NP_000089.1:p.Pro504Leu
NP_001317518.1:p.Pro504Leu
NC_000001.10:g.53676857C>T
NM_000098.2:c.1511C>T
P23786:p.Pro504Leu

Protein change:

P504L

Links:

UniProtKB: P23786#VAR_066567; dbSNP: rs368311455

NCBI 1000 Genomes Browser:

rs368311455

Molecular consequence:

NM_000098.3:c.1511C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330589.2:c.1511C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Carnitine palmitoyltransferase II deficiency (CPT2)
Synonyms:: Carnitine palmitoyl transferase 2 deficiency; Carnitine palmitoyltransferase deficiency type 2
Identifiers:: MONDO: MONDO:0015515; MedGen: C0342790

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915424	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Dec 17, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18306170, 16996287, 17936304, 26537576, 28801073 Citation Link,
SCV000956346	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16996287, 17936304, 18550408, 18306170, 28492532
SCV001431929	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 28, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17936304, 16996287, 26537576, 28801073, 18306170 Citation Link,
SCV002092667	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 25, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency.

Isackson PJ, Bennett MJ, Lichter-Konecki U, Willis M, Nyhan WL, Sutton VR, Tein I, Vladutiu GD.

Mol Genet Metab. 2008 Aug;94(4):422-427. doi: 10.1016/j.ymgme.2008.05.002. Epub 2008 Jun 11.

PubMed [citation]

PMID:: 18550408

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915424.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The CPT2 c.1511C>T (p.Pro504Leu) variant is a missense variant that has been reported in five unrelated individuals with carnitine palmitoyltransferase II (CPT2) deficiency, including in a homozygous state in one individual with the infant form, in a compound heterozygous state in one individual with the infant form, and in a compound heterozygous state in three individuals with the adult form (Yao et al. 2008; Isackson et al. 2008; Corti et al. 2008; Ferreira et al. 2016; Tajima et al. 2017). This variant is reported at a frequency of 0.000072 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated that the variant shows thermal instability and results in reduced enzyme activity compared to wildtype when expressed in COS cells as well as a dominant-negative effect (Yao et al. 2008). Reduced enzyme activity was also observed in muscle from one of the compound heterozyous individuals (Corti et al. 2008). Based on the collective evidence, the p.Pro504Leu variant is classified as pathogenic for carnitine palmitoyltransferase II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000956346.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 504 of the CPT2 protein (p.Pro504Leu). This variant is present in population databases (rs368311455, gnomAD 0.007%). This missense change has been observed in individual(s) with carnitine palmitoyltransferase II deficiency (PMID: 16996287, 17936304, 18550408). ClinVar contains an entry for this variant (Variation ID: 203663). 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%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 18306170). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001431929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: CPT2 c.1511C>T (p.Pro504Leu) 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 3.2e-05 in 246584 control chromosomes (gnomAD). c.1511C>T has been reported in the literature in the compound heterozygous and homozygous states in multiple individuals affected with Carnitine Palmitoyltransferase II Deficiency (e.g. Isackson_2006, Corti_2008, Ferreira_2016, Tajima_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers reduced activity, thermal instability, and short half-live compared to the wild-type (Yao_2008). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002092667.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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