Submissions for variant NM_000098.3(CPT2):c.674G>A (p.Arg225His)

gnomAD frequency: 0.00001  dbSNP: rs794727616

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178041	SCV000230027	uncertain significance	not provided	2016-04-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001563783	SCV001786810	uncertain significance	Carnitine palmitoyl transferase II deficiency, severe infantile form	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001563784	SCV001786811	uncertain significance	Carnitine palmitoyl transferase II deficiency, neonatal form	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001563785	SCV001786812	uncertain significance	Carnitine palmitoyl transferase II deficiency, myopathic form	2021-07-14	criteria provided, single submitter	clinical testing
Invitae	RCV001852205	SCV002134112	uncertain significance	Carnitine palmitoyltransferase II deficiency	2022-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 225 of the CPT2 protein (p.Arg225His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CPT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 197107). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center	RCV001563785	SCV002556332	likely pathogenic	Carnitine palmitoyl transferase II deficiency, myopathic form	2022-07-20	criteria provided, single submitter	clinical testing	The c.674G>A (p.Arg225His) variant identified in trans with a known pathogenic c.338C>T (p.Ser113Leu) variant in this affected patient, is in the fourth coding exon (4/5) of CPT2 gene that is predicted to change a highly conserved Arg to His at codon 225 in CPT2 protein [NM_000098.3, NP_000089.1]. This variant is absent from the ExAC and gnomAD databases, indicating that it is not a common benign variant in the populations represented therein. This variant has been reported as a variant of uncertain significance in ClinVar by outside laboratories (VCV000197107.6). Multiple In silico algorithms predict this variant to be damaging at the genomic and protein level (Polyphen: damaging Score: 1.00, REVEL: Pathogenic Score: 0.976, Provean: Damaging, Score: -4.59, SIFT: Damaging, Score 0). The protein domain in which the variant was identified is predicted to be intolerant to missense substitutions (subRVIS <34.5%). To the best of our knowledge, this variant has not been previously reported in the literature. Given the deleterious nature of the c.674G>A variant as demonstrated by functional assay performed on the patient’s skin fibroblast (abnormal fatty acid profile consistent with CPT2 deficiency), and its absence in the population databases, this heterozygous p.Arg225His variant is reported here as a Likely Pathogenic Variant.
Fulgent Genetics, Fulgent Genetics	RCV002478590	SCV002789082	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	2022-05-11	criteria provided, single submitter	clinical testing