ClinVar Genomic variation as it relates to human health
NM_000098.3(CPT2):c.680C>T (p.Pro227Leu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000098.3(CPT2):c.680C>T (p.Pro227Leu)
Variation ID: 8964 Accession: VCV000008964.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.3 1: 53210354 (GRCh38) [ NCBI UCSC ] 1: 53676026 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 16, 2024 Feb 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000098.3:c.680C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000089.1:p.Pro227Leu missense NM_001330589.2:c.680C>T NP_001317518.1:p.Pro227Leu missense NC_000001.11:g.53210354C>T NC_000001.10:g.53676026C>T NG_008035.1:g.18926C>T P23786:p.Pro227Leu - Protein change
- P227L
- Other names
- p.P227L:CCC>CTC
- Canonical SPDI
- NC_000001.11:53210353:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00031
The Genome Aggregation Database (gnomAD) 0.00039
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 | ||
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HI score
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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. |
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CPT2 | - | - |
GRCh38 GRCh37 |
886 | 1013 |
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. |
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Pathogenic (2) |
no assertion criteria provided
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Oct 11, 2020 | RCV000009526.11 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2024 | RCV000202466.21 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2022 | RCV000185840.21 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000576348.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2022 | RCV002496314.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2023 | RCV003473067.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV003934818.1 |
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. |
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Pathogenic
(Jun 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331529.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Nov 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000238789.8
First in ClinVar: Jul 18, 2015 Last updated: Apr 17, 2019 |
Comment:
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, … (more)
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) (less)
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Pathogenic
(Nov 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520028.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment:
PP3, PP4, PM3, PS3, PS4_moderate
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Pathogenic
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800091.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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. (less)
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Likely pathogenic
(Dec 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Carnitine palmitoyl transferase II deficiency, severe infantile form
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807652.2
First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023 |
Comment:
ACMG classification criteria: PM2 supporting, PM3 strong, PP3 supporting
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Carnitine palmitoyltransferase II deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922502.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Carnitine palmitoyltransferase II deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000756773.8
First in ClinVar: Dec 21, 2015 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Feb 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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CPT2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004752146.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002814378.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Carnitine palmitoyl transferase II deficiency, severe infantile form
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004179396.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Encephalopathy, acute, infection-induced, susceptibility to, 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211034.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029744.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In a premature Haitian infant with neonatal lethal CPT II deficiency (608836), Taroni et al. (1994) identified a homozygous mutation in exon 4 of the … (more)
In a premature Haitian infant with neonatal lethal CPT II deficiency (608836), Taroni et al. (1994) identified a homozygous mutation in exon 4 of the CPT2 gene, resulting in a pro227-to-leu (P227L) substitution. No CPT2 protein was detected by Western blot analysis of fibroblasts, and in vitro analysis demonstrated normal amounts of newly synthesized CPT II, suggesting decreased enzyme stability. CPT II residual activity was measured at less than 15% of normal control values. The parents were heterozygous for the mutation. Isackson et al. (2008) identified a homozygous P227L mutation in an African American patient with lethal neonatal CPT II deficiency. The infant appeared normal at birth but developed hypoglycemia in the nursery. She also had heart block, polycystic kidneys, and seizures, and died at age 14 days. Laboratory studies showed significantly increased plasma carnitine species. Isackson et al. (2008) noted that the P227L substitution is located at the C-terminal end of the beta-2 strand. The authors postulated that the mutation affects enzyme stability, since the affected residue is not near the active site. (less)
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Likely pathogenic
(Apr 24, 2017)
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no assertion criteria provided
Method: clinical testing
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Carnitine palmitoyl transferase II deficiency, severe infantile form
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000678165.2
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
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Pathogenic
(Oct 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Carnitine palmitoyl transferase II deficiency, neonatal form
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469284.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(Mar 19, 2020)
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no assertion criteria provided
Method: clinical testing
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Carnitine palmitoyltransferase II deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002090274.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Carnitine palmitoyltransferase II deficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000153661.3
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Carnitine Palmitoyltransferase II Deficiency. | Adam MP | - | 2019 | PMID: 20301431 |
Diagnostic pitfall in antenatal manifestations of CPT II deficiency. | Boemer F | Clinical genetics | 2016 | PMID: 25827434 |
Neonatal carnitine palmitoyltransferase II deficiency: failure of treatment despite prolonged survival. | Hissink-Muller P | BMJ case reports | 2009 | PMID: 21709843 |
CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. | Isackson PJ | Molecular genetics and metabolism | 2008 | PMID: 18550408 |
Novel mutations associated with carnitine palmitoyltransferase II deficiency. | Taggart RT | Human mutation | 1999 | PMID: 10090476 |
Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency. | Yang BZ | Molecular genetics and metabolism | 1998 | PMID: 9758712 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CPT2 | - | - | - | - |
Taroni, F., Gellera, C., Cavadini, P., Baratta, S., Lamantea, E., Dethlefs, S., DiDonato, S., Reik, R. A., Benke, P. J. Lethal carnitine palmitoyltransferase (CPT) II deficiency in newborns: a molecular-genetic study. (Abstract) Am. J. Hum. Genet. 55 (suppl.): A245-only, 1994. | - | - | - | - |
Text-mined citations for rs74315298 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.