Submissions for variant NM_000098.3(CPT2):c.1148T>A (p.Phe383Tyr)

gnomAD frequency: 0.00001  dbSNP: rs74315295

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000009518	SCV000487431	likely pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2015-11-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000009517	SCV000487432	likely pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2015-11-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000411002	SCV000487433	likely pathogenic	Carnitine palmitoyl transferase II deficiency, neonatal form	2015-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762943	SCV000893366	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, myopathic form; Carnitine palmitoyl transferase II deficiency, neonatal form; Encephalopathy, acute, infection-induced, susceptibility to, 4	2021-07-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000202462	SCV000915423	pathogenic	Carnitine palmitoyltransferase II deficiency	2018-08-09	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the CPT2 c.1148T>A (p.Phe383Tyr) missense variant has been reported in a total of nine individuals with carnitine palmitoyltransferase II (CPT II) deficiency, including in seven with the infantile-onset hepatocardiomuscular form and in two with adult-onset myopathic form (Yamamoto et al. 1998; Wataya et al. 1998; Yasuno et al. 2008). Of those presenting with the hepatocardiomuscular form, one was homozygous for the p.Phe383Tyr variant, three, including two siblings, were compound heterozygous for the variant and a second missense variant, and three were heterozygous with no second variant identified. Of those presenting with the myopathic form, one was homozygous for the p.Phe383Tyr variant and one was heterozygous with no second variant identified. The p.Phe383Tyr variant was also detected in a heterozygous state in three healthy parents of individuals with CPT II. The p.Phe383Tyr variant was absent from 80 Japanese controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Transient expression of the p.Phe383Tyr variant in COS-1 cells revealed an intermediate level of CPT II enzyme activity at approximately 34% of normal, while very low activity was detected, approximately 10% of normal, when the variant was co-expressed with a second missense variant (Wataya et al. 1998). Based on the collective evidence, the p.Phe383Tyr variant is classified as pathogenic for carnitine palmitoyltransferase II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202462	SCV000949879	pathogenic	Carnitine palmitoyltransferase II deficiency	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 383 of the CPT2 protein (p.Phe383Tyr). This variant is present in population databases (rs74315295, gnomAD 0.03%). This missense change has been observed in individual(s) with CPT2 deficiency and CPT2 specific enzyme activity <35% of normal (PMID: 9600456, 18363739, 23700290, 28516040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8958). 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: 9600456). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004159	SCV001162925	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, neonatal form		criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270097	SCV001448915	pathogenic	Seizure; Abnormality of the nervous system	2016-05-18	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000009517	SCV001739497	likely pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2020-02-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000009517	SCV004179481	likely pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473065	SCV004211043	pathogenic	Encephalopathy, acute, infection-induced, susceptibility to, 4	2024-02-13	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000762943	SCV005418237	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, myopathic form; Carnitine palmitoyl transferase II deficiency, neonatal form; Encephalopathy, acute, infection-induced, susceptibility to, 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3_VeryStrong
OMIM	RCV000009517	SCV000029735	pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2007-08-21	no assertion criteria provided	literature only
GeneReviews	RCV000202462	SCV000153664	not provided	Carnitine palmitoyltransferase II deficiency		no assertion provided	literature only
OMIM	RCV000009518	SCV000493926	pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2007-08-21	no assertion criteria provided	literature only
Natera, Inc.	RCV000202462	SCV002090291	pathogenic	Carnitine palmitoyltransferase II deficiency	2020-07-22	no assertion criteria provided	clinical testing