ClinVar Miner

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

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Counsyl RCV000576571 SCV000678026 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2015-11-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185836 SCV000109959 pathogenic not provided 2014-04-16 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
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.
GeneReviews RCV000202499 SCV000153656 pathogenic Carnitine palmitoyltransferase II deficiency 2014-05-15 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000202499 SCV000606920 not provided Carnitine palmitoyltransferase II deficiency no assertion provided phenotyping only 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.
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
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.
Integrated Genetics/Laboratory Corporation of America RCV000202499 SCV000695406 pathogenic Carnitine palmitoyltransferase II deficiency 2016-01-22 criteria provided, single submitter clinical testing
Invitae RCV000202499 SCV000632605 pathogenic Carnitine palmitoyltransferase II deficiency 2019-01-09 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000194764 SCV000223924 pathogenic Carnitine palmitoyltransferase II deficiency, lethal neonatal 2015-01-05 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).
OMIM RCV000009510 SCV000029728 pathogenic Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced 1999-07-01 no assertion criteria provided literature only
Yale Center for Mendelian Genomics,Yale University RCV000662284 SCV000784612 likely pathogenic Rhabdomyolysis 2017-08-05 no assertion criteria provided literature only

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