VCV000008958.27 - ClinVar

NM_000098.3(CPT2):c.1148T>A (p.Phe383Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000098.3(CPT2):c.1148T>A (p.Phe383Tyr)

Variation ID: 8958 Accession: VCV000008958.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 53210822 (GRCh38) [ NCBI UCSC ] 1: 53676494 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Jun 17, 2024	Feb 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000098.3:c.1148T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000089.1:p.Phe383Tyr	missense
NM_001330589.2:c.1148T>A	NP_001317518.1:p.Phe383Tyr	missense
NC_000001.11:g.53210822T>A
NC_000001.10:g.53676494T>A
NG_008035.1:g.19394T>A
	P23786:p.Phe383Tyr

... more HGVS ... less HGVS

Protein change

F383Y

Other names

Canonical SPDI

NC_000001.11:53210821:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA254610 Genetic Testing Registry (GTR): GTR000604056 UniProtKB: P23786#VAR_001396 OMIM: 600650.0007 dbSNP: rs74315295 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CPT2		-	-	GRCh38 GRCh37	899	1027

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Carnitine palmitoyl transferase II deficiency, severe infantile form	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000009517.8
Carnitine palmitoyl transferase II deficiency, myopathic form	Likely pathogenic (2)	criteria provided, single submitter	Nov 30, 2015	RCV000009518.7
Carnitine palmitoyl transferase II deficiency, neonatal form	Likely pathogenic (1)	criteria provided, single submitter	Nov 30, 2015	RCV000411002.2
Carnitine palmitoyltransferase II deficiency	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000202462.16
Abnormality of the nervous system Seizure	Pathogenic (1)	criteria provided, single submitter	May 18, 2016	RCV001270097.1
Carnitine palmitoyl transferase II deficiency, neonatal form Carnitine palmitoyl transferase II deficiency, severe infantile form	Pathogenic (1)	criteria provided, single submitter	-	RCV001004159.1
Carnitine palmitoyl transferase II deficiency, myopathic form Carnitine palmitoyl transferase II deficiency, neonatal form Carnitine palmitoyl transferase II deficiency, severe infantile form Encephalopathy, acute, infection-induced, susceptibility to, 4	Pathogenic (1)	criteria provided, single submitter	Jul 28, 2021	RCV000762943.3
Encephalopathy, acute, infection-induced, susceptibility to, 4	Pathogenic (1)	criteria provided, single submitter	Feb 13, 2024	RCV003473065.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, severe infantile form Affected status: yes Allele origin: germline	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital Accession: SCV001739497.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: East asia Geographic origin: China Testing laboratory: Liwei's Lab
Pathogenic (Jul 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, myopathic form Carnitine palmitoyl transferase II deficiency, severe infantile form Carnitine palmitoyl transferase II deficiency, neonatal form Encephalopathy, acute, infection-induced, susceptibility to, 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893366.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, severe infantile form Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004179481.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Carnitine palmitoyltransferase II deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000949879.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 9600456‚ 18363739‚ 23700290‚ 28516040 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 383 of the CPT2 protein (p.Phe383Tyr). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 383 of the CPT2 protein (p.Phe383Tyr). This variant is present in population databases (rs74315295, gnomAD 0.03%). This missense change has been observed in individual(s) with CPT2 deficiency and CPT2 specific enzyme activity <35% of normal (PMID: 9600456, 18363739, 23700290, 28516040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8958). 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 not expected to disrupt CPT2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 9600456). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy, acute, infection-induced, susceptibility to, 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211043.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Aug 09, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Carnitine palmitoyltransferase II deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915423.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (3) PubMed: 8682496‚ 9600456‚ 18363739 Comment: Across a selection of the available literature, the CPT2 c.1148T>A (p.Phe383Tyr) missense variant has been reported in a total of nine individuals with carnitine palmitoyltransferase … (more) Across a selection of the available literature, the CPT2 c.1148T>A (p.Phe383Tyr) missense variant has been reported in a total of nine individuals with carnitine palmitoyltransferase II (CPT II) deficiency, including in seven with the infantile-onset hepatocardiomuscular form and in two with adult-onset myopathic form (Yamamoto et al. 1998; Wataya et al. 1998; Yasuno et al. 2008). Of those presenting with the hepatocardiomuscular form, one was homozygous for the p.Phe383Tyr variant, three, including two siblings, were compound heterozygous for the variant and a second missense variant, and three were heterozygous with no second variant identified. Of those presenting with the myopathic form, one was homozygous for the p.Phe383Tyr variant and one was heterozygous with no second variant identified. The p.Phe383Tyr variant was also detected in a heterozygous state in three healthy parents of individuals with CPT II. The p.Phe383Tyr variant was absent from 80 Japanese controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Transient expression of the p.Phe383Tyr variant in COS-1 cells revealed an intermediate level of CPT II enzyme activity at approximately 34% of normal, while very low activity was detected, approximately 10% of normal, when the variant was co-expressed with a second missense variant (Wataya et al. 1998). Based on the collective evidence, the p.Phe383Tyr 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, severe infantile form Carnitine palmitoyl transferase II deficiency, neonatal form Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162925.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (May 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizure Abnormality of the nervous system Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448915.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Focal seizures (present) , Focal seizures, afebril (present) , Seizures (present) , Intellectual disability, severe (present) , Intellectual disability (present) , Neurological speech impairment (present) … (more) Focal seizures (present) , Focal seizures, afebril (present) , Seizures (present) , Intellectual disability, severe (present) , Intellectual disability (present) , Neurological speech impairment (present) , Language impairment (present) , Hyperactivity (present) , Attention deficit hyperactivity disorder (present) , Sleep disturbance (present) , Sleep-wake cycle disturbance (present) , Insomnia (present) , Abnormality of the nervous system (present) , Focal clonic seizures (present) , Focal seizures with impairment of consciousness or awareness (present) , Generalized myoclonic seizures (present) , Generalized seizures (present) , Delayed speech and language development (present) , Autistic disorder of childhood onset (present) , Autistic behavior (present) , Developmental regression (present) (less) Sex: male
Likely pathogenic (Nov 30, 2015)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, myopathic form Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487431.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022	Publications: PubMed (7) PubMed: 21227726‚ 25919294‚ 22854105‚ 23700290‚ 18363739‚ 9600456‚ 12673791
Likely pathogenic (Nov 30, 2015)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, severe infantile form Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487432.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022	Publications: PubMed (7) PubMed: 21227726‚ 25919294‚ 22854105‚ 23700290‚ 18363739‚ 9600456‚ 12673791
Likely pathogenic (Nov 30, 2015)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Carnitine palmitoyl transferase II deficiency, neonatal form Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487433.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (7) PubMed: 21227726‚ 25919294‚ 22854105‚ 23700290‚ 18363739‚ 9600456‚ 12673791
Pathogenic (Aug 21, 2007)	no assertion criteria provided Method: literature only	CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029735.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017	Publications: PubMed (2) PubMed: 8682496‚ 17709715 Comment on evidence: For discussion of the phe383-to-tyr (F838Y) mutation in the CPT2 gene that was found in compound heterozygous state in 2 Japanese patients with infantile CPT … (more) For discussion of the phe383-to-tyr (F838Y) mutation in the CPT2 gene that was found in compound heterozygous state in 2 Japanese patients with infantile CPT II deficiency (600649) by Yamamoto et al. (1996), see 600650.0006. Aoki et al. (2007) reported a 21-year-old Japanese woman with the myopathic form of CPT II deficiency (255110) associated with a homozygous F383Y mutation. At age 19 and again at age 21, she had episodes of myalgia, dark urine, and increased serum creatine kinase during viral illnesses. Residual CPT2 activity ranged from 2 to 7% of normal controls, which the authors noted was usually associated with the more severe form of the disorder. Family history revealed a brother and sister who both died as infants. (less)
Pathogenic (Jul 22, 2020)	no assertion criteria provided Method: clinical testing	Carnitine palmitoyltransferase II deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002090291.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Aug 21, 2007)	no assertion criteria provided Method: literature only	CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, MYOPATHIC, STRESS-INDUCED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000493926.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 8682496‚ 17709715 Comment on evidence: For discussion of the phe383-to-tyr (F838Y) mutation in the CPT2 gene that was found in compound heterozygous state in 2 Japanese patients with infantile CPT … (more) For discussion of the phe383-to-tyr (F838Y) mutation in the CPT2 gene that was found in compound heterozygous state in 2 Japanese patients with infantile CPT II deficiency (600649) by Yamamoto et al. (1996), see 600650.0006. Aoki et al. (2007) reported a 21-year-old Japanese woman with the myopathic form of CPT II deficiency (255110) associated with a homozygous F383Y mutation. At age 19 and again at age 21, she had episodes of myalgia, dark urine, and increased serum creatine kinase during viral illnesses. Residual CPT2 activity ranged from 2 to 7% of normal controls, which the authors noted was usually associated with the more severe form of the disorder. Family history revealed a brother and sister who both died as infants. (less)
not provided (-)	no classification provided Method: literature only	Carnitine palmitoyltransferase II deficiency Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000153664.3 First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301431 BookShelf: NBK1253 BookShelf: NBK1253
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Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 383 of the CPT2 protein (p.Phe383Tyr). This variant is present in population databases (rs74315295, gnomAD 0.03%). This missense change has been observed in individual(s) with CPT2 deficiency and CPT2 specific enzyme activity <35% of normal (PMID: 9600456, 18363739, 23700290, 28516040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8958). 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 not expected to disrupt CPT2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 9600456). For these reasons, this variant has been classified as Pathogenic.

Comment:

Across a selection of the available literature, the CPT2 c.1148T>A (p.Phe383Tyr) missense variant has been reported in a total of nine individuals with carnitine palmitoyltransferase II (CPT II) deficiency, including in seven with the infantile-onset hepatocardiomuscular form and in two with adult-onset myopathic form (Yamamoto et al. 1998; Wataya et al. 1998; Yasuno et al. 2008). Of those presenting with the hepatocardiomuscular form, one was homozygous for the p.Phe383Tyr variant, three, including two siblings, were compound heterozygous for the variant and a second missense variant, and three were heterozygous with no second variant identified. Of those presenting with the myopathic form, one was homozygous for the p.Phe383Tyr variant and one was heterozygous with no second variant identified. The p.Phe383Tyr variant was also detected in a heterozygous state in three healthy parents of individuals with CPT II. The p.Phe383Tyr variant was absent from 80 Japanese controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Transient expression of the p.Phe383Tyr variant in COS-1 cells revealed an intermediate level of CPT II enzyme activity at approximately 34% of normal, while very low activity was detected, approximately 10% of normal, when the variant was co-expressed with a second missense variant (Wataya et al. 1998). Based on the collective evidence, the p.Phe383Tyr 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Carnitine Palmitoyltransferase II Deficiency.	Adam MP	-	2019	PMID: 20301431
A newborn case with carnitine palmitoyltransferase II deficiency initially judged as unaffected by acylcarnitine analysis soon after birth.	Yamada K	Molecular genetics and metabolism reports	2017	PMID: 28516040
Metabolic disease in 10 patients with sudden unexpected death in infancy or acute life-threatening events.	Takahashi T	Pediatrics international : official journal of the Japan Pediatric Society	2015	PMID: 25919294
Fatty Acid oxidation disorders in a chinese population in taiwan.	Chien YH	JIMD reports	2013	PMID: 23700290
Acute severe encephalopathy related to human herpesvirus-6 infection in a patient with carnitine palmitoyltransferase 2 deficiency carrying thermolabile variants.	Kobayashi Y	Brain & development	2013	PMID: 22854105
Retrospective review of Japanese sudden unexpected death in infancy: the importance of metabolic autopsy and expanded newborn screening.	Yamamoto T	Molecular genetics and metabolism	2011	PMID: 21227726
Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency.	Yasuno T	Clinical genetics	2008	PMID: 18363739
A Japanese adult form of CPT II deficiency associated with a homozygous F383Y mutation.	Aoki J	Neurology	2007	PMID: 17709715
Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency.	Thuillier L	Human mutation	2003	PMID: 12673791
Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes.	Wataya K	Human mutation	1998	PMID: 9600456
Two novel gene mutations (Glu174-->Lys, Phe383-->Tyr) causing the "hepatic" form of carnitine palmitoyltransferase II deficiency.	Yamamoto S	Human genetics	1996	PMID: 8682496
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Text-mined citations for rs74315295 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000098.3(CPT2):c.1148T>A (p.Phe383Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74315295 ...