Submissions for variant NM_000098.3(CPT2):c.673C>T (p.Arg225Cys)

gnomAD frequency: 0.00001  dbSNP: rs759733220

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317937	SCV001508618	uncertain significance	Carnitine palmitoyltransferase II deficiency	2022-06-14	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 225 of the CPT2 protein (p.Arg225Cys). This variant is present in population databases (rs759733220, gnomAD 0.007%). This missense change has been observed in individual(s) with limb-girdle weakness (PMID: 32528171). ClinVar contains an entry for this variant (Variation ID: 1018610). 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.
Fulgent Genetics, Fulgent Genetics	RCV002486255	SCV002785106	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	2022-05-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003456213	SCV004179392	uncertain significance	Encephalopathy, acute, infection-induced, susceptibility to, 4	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449907	SCV004179393	uncertain significance	Carnitine palmitoyl transferase II deficiency, severe infantile form	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449909	SCV004179394	uncertain significance	Carnitine palmitoyl transferase II deficiency, neonatal form	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449908	SCV004179395	uncertain significance	Carnitine palmitoyl transferase II deficiency, myopathic form	2023-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490184	SCV004240795	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: CPT2 c.673C>T (p.Arg225Cys) 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 8e-06 in 250708 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.673C>T has been reported in the literature in at least one individual with unspecified proximal muscle weakness and/or elevated serum creatine kinase (CK) levels (Topf_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Carnitine Palmitoyltransferase II Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32528171). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.