ClinVar Miner

Submissions for variant NM_000098.3(CPT2):c.110_111dup (p.Ser38fs) (rs754363068)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409793 SCV000487472 likely pathogenic Carnitine palmitoyltransferase II deficiency, myopathic, stress-induced 2015-12-27 criteria provided, single submitter clinical testing
Counsyl RCV000410888 SCV000487473 likely pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2015-12-27 criteria provided, single submitter clinical testing
Counsyl RCV000411956 SCV000487474 likely pathogenic Carnitine palmitoyltransferase II deficiency, lethal neonatal 2015-12-27 criteria provided, single submitter clinical testing
Invitae RCV001042031 SCV001205689 pathogenic Carnitine palmitoyltransferase II deficiency 2020-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser38Alafs*36) in the CPT2 gene. It is expected to result in an absent or disrupted protein product. While this variant is present in population databases (rs754363068), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in combination with another CPT2 variant in individuals affected with carnitine palmitoyltransferase II deficiency (PMID: 10862092, 12673791). ClinVar contains an entry for this variant (Variation ID: 371697). Loss-of-function variants in CPT2 are known to be pathogenic (PMID: 16781677, 16996287). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001042031 SCV001361325 pathogenic Carnitine palmitoyltransferase II deficiency 2021-04-07 criteria provided, single submitter clinical testing Variant summary: CPT2 c.110_111dupGC (p.Ser38AlafsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.3e-05 in 153476 control chromosomes. c.110_111dupGC has been reported in the literature in individuals affected with Carnitine Palmitoyltransferase II Deficiency and in the setting of carrier screening for recessive disorders (example, Bastin_2011, Martin_2000, Thuiller_2003, Lazarin_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal muscle CPT residual enzyme activity in a compound heterozygous genotype (Martin_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV001042031 SCV001461211 pathogenic Carnitine palmitoyltransferase II deficiency 2020-09-16 no assertion criteria provided clinical testing
GeneDx RCV001570857 SCV001795219 pathogenic not provided 2020-01-07 no assertion criteria provided 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Also denoted as 36-38 insGC due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31589614, 10862092, 22975760)

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