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

dbSNP: rs397509431

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000185837	SCV000109955	pathogenic	not provided	2012-07-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000185837	SCV000238786	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as 413delAG, 1237delAG and c.del1238_1239AG; This variant is associated with the following publications: (PMID: 22975760, 25827434, 19335026, 28871440, 34958143, 31428121, 11477613, 10090476)
Invitae	RCV000202516	SCV000632584	pathogenic	Carnitine palmitoyltransferase II deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys414Thrfs*7) in the CPT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPT2 are known to be pathogenic (PMID: 16781677, 16996287). This variant is present in population databases (rs397509431, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with CPT2-deficiency, and has been observed to occur in cis with the p.Phe448Leu missense change (PMID: 10090476, 12673791, 12707442, 21913903). This variant is also known as c.del1238_1239AG/Q413fs. ClinVar contains an entry for this variant (Variation ID: 92430). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202516	SCV000695404	pathogenic	Carnitine palmitoyltransferase II deficiency	2016-06-10	criteria provided, single submitter	clinical testing	Variant summary: The CPT2 c.1239_1240delGA (p.Lys414Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent CPT2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 13/121214 (1/9328), which does not exceed the estimated maximal expected allele frequency for a pathogenic CPT2 variant of 1/9328 (0.0015811). The variant of interest has been reported in multiple affected individuals via publications and has been indicated to be a part of a complex allele with another pathogenic CPT2 variant, p.F448L in multiple affected individuals. In addition, multiple clinical laboratories/databases cite the variant as "pathogenic." Therefore, taking all available lines of evidence, the variant of interest is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000576522	SCV001194174	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2019-12-19	criteria provided, single submitter	clinical testing	NM_000098.2(CPT2):c.1239_1240delGA(K414Tfs*7) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency and is associated with the neonatal form of disease. Sources cited for classification include the following: PMID 12673791, 16996287, 10090476‚Äé, 18550408 and 15642848. Classification of NM_000098.2(CPT2):c.1239_1240delGA(K414Tfs*7) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000185837	SCV001335204	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000185837	SCV002019725	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002225079	SCV002503836	pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2020-10-26	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002225079	SCV002767254	pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2021-05-06	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV002490673	SCV002780858	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, myopathic form; Carnitine palmitoyl transferase II deficiency, neonatal form; Encephalopathy, acute, infection-induced, susceptibility to, 4	2022-05-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000576522	SCV004179492	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474675	SCV004211028	pathogenic	Encephalopathy, acute, infection-induced, susceptibility to, 4	2023-10-29	criteria provided, single submitter	clinical testing
GeneReviews	RCV000202516	SCV000153665	not provided	Carnitine palmitoyltransferase II deficiency		no assertion provided	literature only
Natera, Inc.	RCV000202516	SCV001454238	pathogenic	Carnitine palmitoyltransferase II deficiency	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000202516	SCV004228577	not provided	Carnitine palmitoyltransferase II deficiency		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-11-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.