ClinVar Genomic variation as it relates to human health

The CPT2 c.1511C>T (p.Pro504Leu) variant is a missense variant that has been reported in five unrelated individuals with carnitine palmitoyltransferase II (CPT2) deficiency, including in a homozygous state in one individual with the infant form, in a compound heterozygous state in one individual with the infant form, and in a compound heterozygous state in three individuals with the adult form (Yao et al. 2008; Isackson et al. 2008; Corti et al. 2008; Ferreira et al. 2016; Tajima et al. 2017). This variant is reported at a frequency of 0.000072 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated that the variant shows thermal instability and results in reduced enzyme activity compared to wildtype when expressed in COS cells as well as a dominant-negative effect (Yao et al. 2008). Reduced enzyme activity was also observed in muscle from one of the compound heterozyous individuals (Corti et al. 2008). Based on the collective evidence, the p.Pro504Leu 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.

Variant summary: CPT2 c.1511C>T (p.Pro504Leu) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246584 control chromosomes (gnomAD). c.1511C>T has been reported in the literature in the compound heterozygous and homozygous states in multiple individuals affected with Carnitine Palmitoyltransferase II Deficiency (e.g. Isackson_2006, Corti_2008, Ferreira_2016, Tajima_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers reduced activity, thermal instability, and short half-live compared to the wild-type (Yao_2008). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 504 of the CPT2 protein (p.Pro504Leu). This variant is present in population databases (rs368311455, gnomAD 0.007%). This missense change has been observed in individual(s) with carnitine palmitoyltransferase II deficiency (PMID: 16996287, 17936304, 18550408). ClinVar contains an entry for this variant (Variation ID: 203663). 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%. Experimental studies have shown that this missense change affects CPT2 function (PMID: 18306170). For these reasons, this variant has been classified as Pathogenic.

PP3, PP4, PM3_strong, PS3_moderate