ClinVar Miner

Submissions for variant NM_000098.3(CPT2):c.1239_1240del (p.Lys414fs) (rs397509431)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185837 SCV000109955 pathogenic not provided 2012-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000185837 SCV000238786 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The c.1239_1240delGA variant in the CPT2 gene has been reported previously, as 413 delAG using alternate nomenclature, in as part of a complex allele with another variant, F448L, in cis and in the presence of a second CPT2 variant on the opposite allele, in individuals with carnitine palmitoyltransferase II (CPT II) deficiency in muscle or lymphoblasts and symptoms of exercise intolerance, pain, and myoglobinuria (Taggart et al., 1999). The c.1239_1240delGA variant complex allele, has also been reported in the homozygous state, as 1237delAG and as c.del1238_1239AG using alternate nomenclature, in siblings from two unrelated Ashkenazi Jewish families, who presented prenatally with renal and brain abnormalities (Elpeleg et al., 2001; Meir et al., 2009; Boemer et al. (2016). The c.1239_1240delGA variant is the second most common CPT2 variant and is found in approximately 20% of mutant alleles in patients of Ashkenazi Jewish ancestry (Taggart et al., 1999). The c.1239_1240delGA variant causes a frameshift starting with codon Lysine 414, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Lys414ThrfsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1239_1240delGA variant is observed in 13/66658 (0.0195%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). We interpret c.1239_1240delGA as a pathogenic variant.
Invitae RCV000202516 SCV000632584 pathogenic Carnitine palmitoyltransferase II deficiency 2020-10-20 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 4 of the CPT2 mRNA (c.1239_1240delGA), causing a frameshift at codon 414. This creates a premature translational stop signal (p.Lys414Thrfs*7) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPT2 are known to be pathogenic. This particular variant has been reported in the literature and is a common cause of 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 in the literature. ClinVar contains an entry for this variant (Variation ID: 60702). 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 Women's Health, Inc. RCV000576522 SCV001194174 pathogenic Carnitine palmitoyltransferase II deficiency, infantile 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 Praxis fuer Humangenetik Tuebingen RCV000185837 SCV001335204 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
GeneReviews RCV000202516 SCV000153665 pathogenic Carnitine palmitoyltransferase II deficiency 2017-03-16 no assertion criteria provided literature only
Natera, Inc. RCV000202516 SCV001454238 pathogenic Carnitine palmitoyltransferase II deficiency 2020-09-16 no assertion criteria provided clinical testing

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