Submissions for variant NM_000098.3(CPT2):c.691C>T (p.Arg231Trp)

gnomAD frequency: 0.00004  dbSNP: rs373638740

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674663	SCV000800042	uncertain significance	Carnitine palmitoyl transferase II deficiency, severe infantile form	2018-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796802	SCV000936330	likely pathogenic	Carnitine palmitoyltransferase II deficiency	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 231 of the CPT2 protein (p.Arg231Trp). This variant is present in population databases (rs373638740, gnomAD 0.006%). This missense change has been observed in individuals with carnitine palmitoyltransferase II deficiency and/or CPT2-related conditions (PMID: 16996287, 24398345, 24602495, 30455135). ClinVar contains an entry for this variant (Variation ID: 203661). 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 expected to disrupt CPT2 protein function with a positive predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001092683	SCV001249307	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001092683	SCV001715288	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230439	SCV003928783	uncertain significance	not specified	2023-04-12	criteria provided, single submitter	clinical testing	Variant summary: CPT2 c.691C>T (p.Arg231Trp) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of 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 3.6e-05 in 250840 control chromosomes. c.691C>T has been reported in the literature in individuals affected with Carnitine Palmitoyltransferase II Deficiency. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=4, pathogenic n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003474940	SCV004211033	pathogenic	Encephalopathy, acute, infection-induced, susceptibility to, 4	2024-03-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000796802	SCV001454230	uncertain significance	Carnitine palmitoyltransferase II deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927721	SCV004741138	likely pathogenic	CPT2-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The CPT2 c.691C>T variant is predicted to result in the amino acid substitution p.Arg231Trp. This variant has been reported with a second CPT2 variant in individuals with carnitine palmitoyltransferase II deficiency; however, pathogenicity was not established (Isackson et al. 2006. PubMed ID: 16996287; Table 4, Joshi et al. 2013. PubMed ID: 24398345; Table 1, Lehmann and Zierz. 2014. PubMed ID: 24602495). This variant was observed in the compound heterozygous state with a nonsense CPT2 variant in an individual undergoing testing with a CPT2-related disease phenotype (Internal Data, PreventionGenetics). This variant is reported in 0.0062% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.