Submissions for variant NM_000098.3(CPT2):c.1025T>C (p.Met342Thr)

gnomAD frequency: 0.00110  dbSNP: rs144658100

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000427828	SCV000510627	uncertain significance	not provided	2017-01-31	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079544	SCV000632582	likely benign	Carnitine palmitoyltransferase II deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000667275	SCV000791697	uncertain significance	Carnitine palmitoyl transferase II deficiency, severe infantile form	2017-05-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763959	SCV000894910	uncertain significance	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	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079544	SCV001256742	uncertain significance	Carnitine palmitoyltransferase II deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000427828	SCV001982174	uncertain significance	not provided	2023-04-02	criteria provided, single submitter	clinical testing	Reported in trans with a second variant in CPT2 in an infant with a complex phenotype including Tetraology of Fallot, Meckels diverticulum, micro vesicular steatosis and hypotrophy of liver, mild s-shaped scoliosis with right thoracic convexity, hypotonia and hypoxemic spells (Josifovska et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503134, 29429925, 28492532)
Mayo Clinic Laboratories, Mayo Clinic	RCV000427828	SCV002542208	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289546	SCV002578915	uncertain significance	Carnitine palmitoyl transferase II deficiency, myopathic form	2022-03-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000427828	SCV003799457	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	The CPT2 1025T>C; p.Met342Thr variant (rs144658100) is reported in the literature in an individual affected with a dyslipidemia, but without clear disease association (Johansen 2014). This variant is also reported in ClinVar (Variation ID: 376799), and is found in the general population with an overall allele frequency of 0.11% (321/282498 alleles) in the Genome Aggregation Database. The methionine at codon 342 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.847). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Johansen CT et al. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res. 2014 Apr;55(4):765-72. PMID: 24503134.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387839	SCV004099933	likely benign	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: CPT2 c.1025T>C (p.Met342Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251094 control chromosomes, predominantly at a frequency of 0.0023 within the Finnish European subpopulation in the gnomAD database. In addition, the variant was found with even higher in certain European subpopulations, including the Estonian (0.007654), and Bulgarian (0.007121). These subpopulation frequencies are significantly higher than estimated maximum expected for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency (0.0016), suggesting that the variant might be benign. To our knowledge, no occurrence of c.1025T>C in individuals affected with Carnitine Palmitoyltransferase II Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=9) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003957893	SCV004784982	likely benign	CPT2-related disorder	2022-07-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004022260	SCV004849778	uncertain significance	Inborn genetic diseases	2021-02-22	criteria provided, single submitter	clinical testing	The c.1025T>C (p.M342T) alteration is located in exon 4 (coding exon 4) of the CPT2 gene. This alteration results from a T to C substitution at nucleotide position 1025, causing the methionine (M) at amino acid position 342 to be replaced by a threonine (T). The p.M342T alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001079544	SCV001454126	uncertain significance	Carnitine palmitoyltransferase II deficiency	2019-12-30	no assertion criteria provided	clinical testing