ClinVar Miner

Submissions for variant NM_000098.3(CPT2):c.338C>T (p.Ser113Leu) (rs74315294)

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185836 SCV000109959 pathogenic not provided 2014-04-16 criteria provided, single submitter clinical testing
GeneDx RCV000185836 SCV000238785 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The S113L variant is the most common CPT2 variant found in approximately 60% of mutant alleles in European patients with the adult myopathic form of carnitine palmitoyltransferase II (CPT2) deficiency (Bonnefont et al., 2004). S113L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional analysis demonstrates that the S113L variant is associated with a significant reduction in enzyme activity (Taroni et al., 1993). We interpret S113L as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000202499 SCV000358097 pathogenic Carnitine palmitoyltransferase II deficiency 2017-04-27 criteria provided, single submitter clinical testing The CPT2 c.338C>T (p.Ser113Leu) missense variant is the most commonly occurring pathogenic variant in the CPT2 gene, accounting for approximately 60% of disease alleles (Wieser et al. 2014). Across a small selection of the available literature, the p.Ser113Leu variant was identified in a total of 77 individuals with carnitine palmitoyltransferase II deficiency, including 38 homozygotes, 18 compound heterozygotes, and 21 heterozygotes in whom a second variant was not reported (Taroni et al. 1993; Bonnefont et al. 1996; Martin et al. 1999; Anichini et al. 2011; Fanin et al. 2012; Shima et al. 2016). The variant was also found in nine unaffected heterozygous carriers (Martin et al. 1999). The p.Ser113Leu variant was absent from 64 controls but is reported at a frequency of 0.00201 in the European (non-Finnish) population of the Exome Aggregation Consortium. Taroni et al. (1993) demonstrated that the p.Ser113Leu variant displayed significantly reduced CPT II activity but similar enzyme synthesis as compared to wild type when transiently expressed in COS1 cells. Additionally, steady-state levels of CPT II from lymphoblasts from an individual homozygous for the p.Ser113Leu variant were significantly decreased as compared to control cells, though normal biosynthesis of CPT II was observed. Bonnefont et al. (1996) showed a reduction to 20% of wild type of residual CPT II activity in fibroblasts from an individual homozygous for the p.Ser113Leu variant. Based on the collective evidence, the p.Ser113Leu 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185836 SCV000610061 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515252 SCV000611187 pathogenic Carnitine palmitoyltransferase II deficiency, infantile; Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced; Carnitine palmitoyltransferase II deficiency, lethal neonatal; Encephalopathy, acute, infection-induced, 4, susceptibility to 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000202499 SCV000632605 pathogenic Carnitine palmitoyltransferase II deficiency 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 113 of the CPT2 protein (p.Ser113Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs74315294, ExAC 0.2%). This variant is clearly defined as a CPT2 deficiency causative allele. It has been reported as the most common cause of CPT2 deficiency in individuals of European ancestry (PMID: 10090476, 12673791, 12707442, 21913903, 15642848, 10398215, 15776096, 9309694) and has been associated with the adult onset form of the disease (PMID: 17936304). In addition, it has been observed to segregate with disease in one family (PMID: 8786066). ClinVar contains an entry for this variant (Variation ID: 8953). Experimental studies have found that this missense change reduces the catalytic activity of the CPT2 protein, alters the thermal stability of the CPT2 protein, and/or impacts the regulation of CPT2 by certain metabolites (PMID: 8358442, 2647738, 27123472). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202499 SCV000695406 pathogenic Carnitine palmitoyltransferase II deficiency 2016-01-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000202499 SCV000711454 pathogenic Carnitine palmitoyltransferase II deficiency 2014-10-02 criteria provided, single submitter clinical testing The p.Ser113Leu variant in CPT2 is the most common variant associated with late- onset carnitine palmitoyltransferase deficiency (myopathic form); most of the pa tients reported to date (>14) were homozygous (Taroni 1993, Bonnefont 1996, Mart in 1999). The p.Ser113Leu variant has been identified in 0.2% (134/66568) of Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs74315294). Although this variant has been seen in the gener al population, its frequency is low enough to be consistent with a recessive car rier frequency. Biochemical characterization and in vitro functional studies als o provide evidence that the p.Ser113Leu variant may impact protein function (Tar oni 1993, Bonnefont 1996). In summary, this variant meets criteria to be classif ied as pathogenic for carnitine palmitoyltransferase II deficiency in an autosom al recessive manner. It should be noted that a few heterozygous carriers of this variant have been reported with mild symptoms (Taggert 1999, Kaufmann 1997).
Ambry Genetics RCV000624845 SCV000741685 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000576571 SCV000807602 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a frameshift mutation in a 1-year-old female with IUGR, global delays, spastic tetraparesis, brain calcifications and leukomalacia, and a similarly affected brother (who was a single heterozygote; did not carry the frameshift mutation). Heterozygotes are expected to be asymptomatic carriers.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000202499 SCV000930233 uncertain significance Carnitine palmitoyltransferase II deficiency 2019-04-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004157 SCV001162923 pathogenic Carnitine palmitoyltransferase II deficiency, infantile; Carnitine palmitoyltransferase II deficiency, lethal neonatal criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000576571 SCV001194229 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2019-10-18 criteria provided, single submitter clinical testing NM_000098.2(CPT2):c.338C>T(S113L) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency. Please note that the S113L variant is associated with the myopathic form of carnitine palmitoyltransferase II deficiency. Disease phenotype is dependent on, but not necessarily predicted by, the combination of variants inherited. Sources cited for classification include the following: PMID 21913903, 16996287, 15642848 and 835844. Classification of NM_000098.2(CPT2):c.338C>T(S113L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185836 SCV001249306 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000185836 SCV001446835 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000009510 SCV001448889 pathogenic Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced 2017-05-03 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000185836 SCV001475801 pathogenic not provided 2019-11-22 criteria provided, single submitter clinical testing The best available variant frequency is 1-3 times higher than the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant appears to segregate with disease in at least one family.
Pars Genome Lab RCV000576571 SCV001652884 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000185836 SCV001715286 pathogenic not provided 2021-03-04 criteria provided, single submitter clinical testing PS3, PS4, PM2, PP5
Nilou-Genome Lab RCV000576571 SCV001810369 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2021-07-22 criteria provided, single submitter clinical testing
OMIM RCV000009510 SCV000029728 pathogenic Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced 1999-07-01 no assertion criteria provided literature only
GeneReviews RCV000202499 SCV000153656 pathogenic Carnitine palmitoyltransferase II deficiency 2017-03-16 no assertion criteria provided literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000194764 SCV000223924 pathogenic Carnitine palmitoyltransferase II deficiency, lethal neonatal 2015-01-05 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000202499 SCV000606920 not provided Carnitine palmitoyltransferase II deficiency no assertion provided phenotyping only Variant interpretted as Pathogenic and reported most recently on 11-25-2015 by Lab or GTR ID 500068. The variant was also interpretted as Pathogenic and reported on 11/17/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Yale Center for Mendelian Genomics,Yale University RCV000662284 SCV000784612 likely pathogenic Rhabdomyolysis 2017-08-05 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000202499 SCV001142299 pathogenic Carnitine palmitoyltransferase II deficiency 2020-01-06 no assertion criteria provided curation NM_000098.2:c.338C>T in the CPT2 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Ser113Leu (NM_000098.2:c.338C>T) variant has been observed to segregate with disease in one family with three affected individuals and two unaffected individuals (PMID: 8786066). Martin MA et al performed molecular analysis in a group of 14 Spanish patients with CPT II deficiency from ten unrelated families. The S113L mutation was observed in 8 of the 14 patients studied. Seven patients were homozygous for the mutation (PMID: 10398215). In addition, Anichini A et al reported that p.Ser113Leu was identified in five homozygote patients and in compound heterozygosity in five cases: c.338C>T (p.Ser113Leu)/c.1724T>C (p.Leu575Pro); c.338C>T (p.Ser113Leu)/c.1547T>C (p.Phe516Ser); c.338C>T (p.Ser113Leu) c.1348A>T (p.Arg450Stop); c.338C>T (p.Ser113Leu)/c.1932insA (p.E645RfsX4); c.338C>T (p.Ser113Leu)/c.1239G>A (p.Gln413Gln) (PMID: 20810031). Functional analysis demonstrates that the c.338C>T variant is associated with a significant reduction in enzyme activity (PMID:8358442). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP1_Moderate; PP3.
Institute of Human Genetics, Klinikum rechts der Isar RCV000576571 SCV001150076 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2020-03-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000202499 SCV001461214 pathogenic Carnitine palmitoyltransferase II deficiency 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000185836 SCV001809499 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000185836 SCV001952033 pathogenic not provided no assertion criteria provided clinical testing

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