NM_000098.3(CPT2):c.1239_1240del (p.Lys414fs) AND Carnitine palmitoyl transferase II deficiency, myopathic form

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 6, 2021
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:: RCV002225079.11

Allele description [Variation Report for NM_000098.3(CPT2):c.1239_1240del (p.Lys414fs)]

NM_000098.3(CPT2):c.1239_1240del (p.Lys414fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_000098.3(CPT2):c.1239_1240del (p.Lys414fs)

HGVS:

NC_000001.11:g.53210913_53210914del
NG_008035.1:g.19485_19486del
NM_000098.3:c.1239_1240delMANE SELECT
NM_001330589.2:c.1239_1240del
NP_000089.1:p.Lys414fs
NP_001317518.1:p.Lys414fs
NC_000001.10:g.53676584_53676585del
NC_000001.10:g.53676585_53676586del
NM_000098.2:c.1238_1239del
NM_000098.2:c.1238_1239delAG
NM_000098.2:c.1239_1240delGA
NM_000098.3:c.1239_1240delGAMANE SELECT
c.1238_1239delAG (p.Lys414Thrfs*7)
p.K414TfsX7

Protein change:

K414fs

Links:

OMIM: 600650.0009; dbSNP: rs397509431

NCBI 1000 Genomes Browser:

rs397509431

Molecular consequence:

NM_000098.3:c.1239_1240del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330589.2:c.1239_1240del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Carnitine palmitoyl transferase II deficiency, myopathic form
Synonyms:: CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, ADULT-ONSET; CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, MYOPATHIC; CPT II DEFICIENCY, MYOPATHIC; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009704; MedGen: C1833508; Orphanet: 157; Orphanet: 228302; OMIM: 255110

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002503836	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 26, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10090476, 11477613, 12410208, 20301431, 25741868
SCV002767254	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21913903, 32295037, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503836

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 26, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002767254

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Novel mutations associated with carnitine palmitoyltransferase II deficiency.

Taggart RT, Smail D, Apolito C, Vladutiu GD.

Hum Mutat. 1999;13(3):210-20.

PubMed [citation]

PMID:: 10090476

Antenatal presentation of carnitine palmitoyltransferase II deficiency.

Elpeleg ON, Hammerman C, Saada A, Shaag A, Golzand E, Hochner-Celnikier D, Berger I, Nadjari M.

Am J Med Genet. 2001 Aug 1;102(2):183-7.

PubMed [citation]

PMID:: 11477613

See all PubMed Citations (7)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503836.2

#	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 is a deletion of 2 bp in exon 4 (of 5) of CPT2 that is predicted to create a premature termination codon at position 420 (p.(Lys414Thrfs*7)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinVar). The variant is present in a large population cohort at a frequency of 0.02%, which is consistent with recessive disease (rs397509431, 53/251,372 alleles, 0 homozygotes in gnomAD v2.1). It is more common in the Ashkenazi Jewish population at a frequency of 0.5% (47/10,080 alleles in gnomAD v2.1). The variant is the second most commonly occurring pathogenic variant in Europeans, always in cis with NM_000098.3:c.1342T>C, p.Phe448Leu (PMID: 20301431). The variant has been identified in the homozygous state and with a second pathogenic allele in multiple cases with phenotypes ranging from the lethal neonatal, infantile, and myopathic forms of CPT II deficiency, and segregates with disease in at least one family (PMID: 10090476, 11477613, 12410208). CPT II deficiency has been demonstrated in patient cells from homozygous cases, including both enzyme activity and long-chain fatty-acid oxidation (PMID: 11477613). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PM2, PP1, PP4.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767254.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal, infantile and stress-induced myopathic CPT II deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. This gene is generally considered to be associated with an autosomal recessive condition, but some cases of manifesting carriers have been reported for the myopathic of CPT II deficiency (PMID: 32295037). (I) 0115 - Variants in this gene are known to have variable expressivity. The myopathic form of this condition can manifest from infancy to adulthood and variable onset, frequency, and severity of symptoms have been reported (PMID: 32295037). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (53 heterozygotes, 0 homozygotes) and is enriched in the Ashkenazi Jewish sub-population. (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with CPT II deficiency (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with the myopathic form of CPT II deficiency (ClinVar, PMID: 21913903). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 9, 2024

ClinVar

Relating variation to medicine