Submissions for variant NM_000098.3(CPT2):c.1342T>C (p.Phe448Leu)

gnomAD frequency: 0.00021  dbSNP: rs74315297

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178040	SCV000230026	other	not provided	2015-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000430397	SCV000512764	benign	not specified	2015-04-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000202478	SCV000632585	uncertain significance	Carnitine palmitoyltransferase II deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 448 of the CPT2 protein (p.Phe448Leu). This variant is present in population databases (rs74315297, gnomAD 0.5%). This missense change has been observed in individual(s) with autosomal recessive carnitine palmitoyltransferase II deficiency. It is often reported in cis with the truncating variant c.1239_1240del (p.Lys414Thrfs*7), and this haplotype is a common cause of CPT2-deficiency (PMID: 10090476, 12673791, 12707442, 21913903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV001810398	SCV002060051	uncertain significance	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, myopathic form; Carnitine palmitoyl transferase II deficiency, neonatal form	2021-10-27	criteria provided, single submitter	clinical testing	NM_000098.2(CPT2):c.1342T>C(F448L) is a missense variant classified as a variant of uncertain significance in the context of carnitine palmitoyltransferase II deficiency. F448L has been observed in cases with relevant disease (PMID: 12673791). Functional assessments of this variant are not available in the literature. F448L has been observed in population frequency databases (gnomAD: ASJ 0.49%). In summary, there is insufficient evidence to classify NM_000098.2(CPT2):c.1342T>C(F448L) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
GeneReviews	RCV000202478	SCV000153667	uncertain significance	Carnitine palmitoyltransferase II deficiency	2017-03-16	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV000202478	SCV004228578	not provided	Carnitine palmitoyltransferase II deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-11-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.