Submissions for variant NM_001876.4(CPT1A):c.1784G>A (p.Arg595Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002952555	SCV003267347	uncertain significance	Carnitine palmitoyl transferase 1A deficiency	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 595 of the CPT1A protein (p.Arg595Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs763226691, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with CPT1A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV002952554	SCV003574021	uncertain significance	Inborn genetic diseases	2021-08-16	criteria provided, single submitter	clinical testing	The c.1784G>A (p.R595Q) alteration is located in exon 15 (coding exon 14) of the CPT1A gene. This alteration results from a G to A substitution at nucleotide position 1784, causing the arginine (R) at amino acid position 595 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM	RCV002952555	SCV004047893	uncertain significance	Carnitine palmitoyl transferase 1A deficiency		criteria provided, single submitter	clinical testing	The c.1784G>A (p.Arg595Gln) missense variant in CPT1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg595Gln variant is reported with the allele frequency (0.0007%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 595 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg595Gln in CPT1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).