ClinVar Miner

Submissions for variant NM_000098.3(CPT2):c.680C>T (p.Pro227Leu) (rs74315298)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185840 SCV000238789 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The P227L missense variant has been previously reported in the homozygous state in individuals with carnitine palmitoyltransferase II (CPT2) deficiency (Yang et al., 1998; Isackson et al., 2008; Hissink- Muller et al., 2009; Boemer et al., 2016). Homozygosity for this variant is often associated with the lethal neonatal form of CPT2 deficiency (Wieser et al., 2017). The P227L variant has also been reported in the heterozygous state in an individual with neonatal CPT2 deficiency; this individual was also found to harbor another variant in the CPT2 gene (Yang et al., 1998). The P227L variant is observed in 24/23968 (0.1%) alleles from individuals of African background, and 24/276470 (0.009%) total alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The P227L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret P227L as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185840 SCV000331529 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing
Invitae RCV000202466 SCV000756773 pathogenic Carnitine palmitoyltransferase II deficiency 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 227 of the CPT2 protein (p.Pro227Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs74315298, ExAC 0.1%). This variant has been reported as homozygous or in combination with another CPT2 variant in two individuals affected with carnitine palmitoyltransferase II deficiency (PMID: 18550408, 25827434) and in two individuals suspected to have this condition (PMID: 9758712, 21709843). ClinVar contains an entry for this variant (Variation ID: 8964). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009526 SCV000029744 pathogenic Carnitine palmitoyltransferase II deficiency, lethal neonatal 2008-08-01 no assertion criteria provided literature only
GeneReviews RCV000202466 SCV000153661 pathogenic Carnitine palmitoyltransferase II deficiency 2017-03-16 no assertion criteria provided literature only
Counsyl RCV000576348 SCV000678165 likely pathogenic Carnitine palmitoyltransferase II deficiency, infantile 2017-04-24 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000009526 SCV001469284 pathogenic Carnitine palmitoyltransferase II deficiency, lethal neonatal 2020-10-11 no assertion criteria provided clinical testing

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