Submissions for variant NM_000098.3(CPT2):c.1507C>T (p.Arg503Cys)

gnomAD frequency: 0.00001  dbSNP: rs74315296

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202513	SCV000822556	pathogenic	Carnitine palmitoyltransferase II deficiency	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 503 of the CPT2 protein (p.Arg503Cys). This variant is present in population databases (rs74315296, gnomAD 0.003%). This missense change has been observed in individual(s) with CPT2-related conditions (PMID: 10090476, 10873395, 17372854, 19762733, 21913903; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8959). 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%. This variant disrupts the p.Arg503 amino acid residue in CPT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004160	SCV001162926	likely pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form; Carnitine palmitoyl transferase II deficiency, neonatal form		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490348	SCV002809887	likely 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	2021-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV003317032	SCV004021707	likely pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Reported as heterozygous in several unrelated individuals with myopathic symptoms with reduced CPT2 activity in fibroblasts; a second variant in CPT2 was not identified in these individuals (Taggart RT et al., 1999; Vladutiu GD et al., 2000; Fanin et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); 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: 22975760, 17372854, 18550408, 12673791, 14615409, 10090476, 16996287, 21913903, 19762733, 34426522, 35641460, 25929793, 10873395, 32295037)
Genome-Nilou Lab	RCV003450624	SCV004179566	likely pathogenic	Carnitine palmitoyl transferase II deficiency, severe infantile form	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473066	SCV004211047	likely pathogenic	Encephalopathy, acute, infection-induced, susceptibility to, 4	2024-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202513	SCV004813151	likely pathogenic	Carnitine palmitoyltransferase II deficiency	2024-02-16	criteria provided, single submitter	clinical testing	Variant summary: CPT2 c.1507C>T (p.Arg503Cys) 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 4e-06 in 247112 control chromosomes (gnomAD). c.1507C>T has been reported in the literature as a biallelic genotype in at least two individuals affected with Carnitine Palmitoyltransferase II Deficiency and in several other affected individuals in whom no second variant was identified, but who had CPT activity below the normal range (e.g. Taggart_1999, Thuiller_2003, Spiegel_2007, Hogan_2009, Fanin_2012, ). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21913903, 19762733, 17372854, 10090476, 12673791, 10873395). ClinVar contains an entry for this variant (Variation ID: 8959). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000009519	SCV000029737	pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2000-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000202513	SCV000153668	not provided	Carnitine palmitoyltransferase II deficiency		no assertion provided	literature only
Natera, Inc.	RCV000202513	SCV002092666	likely pathogenic	Carnitine palmitoyltransferase II deficiency	2020-11-25	no assertion criteria provided	clinical testing