Submissions for variant NM_000098.3(CPT2):c.1436A>T (p.Tyr479Phe)

gnomAD frequency: 0.00010  dbSNP: rs749895856

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626609	SCV000747310	likely pathogenic	Genu valgum; Pes planus; Hyperextensibility of the finger joints; Generalized hypotonia; Myopathic facies; Hyperextensible hand joints; Hyperextensibility at elbow	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000696870	SCV000825450	likely pathogenic	Carnitine palmitoyltransferase II deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 479 of the CPT2 protein (p.Tyr479Phe). This variant is present in population databases (rs749895856, gnomAD 0.009%). This missense change has been observed in individuals with carnitine palmitoyltransferase II deficiency (PMID: 12707442, 15642848). ClinVar contains an entry for this variant (Variation ID: 523331). 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%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 34063237). This variant disrupts the p.Tyr479 amino acid residue in CPT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15642848, 18925671). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics Inc	RCV000711320	SCV000841661	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196658	SCV001367278	likely pathogenic	Carnitine palmitoyl transferase II deficiency, neonatal form	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731819	SCV001983761	uncertain significance	not specified	2022-05-20	criteria provided, single submitter	clinical testing	Variant summary: CPT2 c.1436A>T (p.Tyr479Phe) results in a conservative amino acid change located in the Choline/carnitine acyltransferase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250996 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency (4e-05 vs 0.0016), allowing no conclusion about variant significance. c.1436A>T has been reported in the literature in at least one compound heterozygous individual affected with Carnitine Palmitoyltransferase II Deficiency (Wiser_2003). Experimental studies have shown the initial enzyme activity of the variant was similar to wild-type, but that the activity half-lives of the variant at different temperatures were reduced, albeit more midly than for other variants (Meinhardt_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified the variant as VUS while one classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV000696870	SCV001454240	uncertain significance	Carnitine palmitoyltransferase II deficiency	2020-09-16	no assertion criteria provided	clinical testing