ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the SLC22A5 protein (p.Arg282Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985, 21922592). ClinVar contains an entry for this variant (Variation ID: 25401). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC22A5 protein function. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 16652335). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Published functional studies found this variant is associated with significantly impaired carnitine transport (Amat di San Filippo C et al., 2006; Frigeni M et al. 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16652335, 28841266, 32371215, 33757571, 21922592, 23430858, 16602102, 26828774, 23379544, 20574985, 23520115, 20074989, 33181153, 35095998)

The c.845G>A (p.R282Q) alteration is located in exon 5 (coding exon 5) of the SLC22A5 gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.845G>A alteration has been reported in homozygous and compound heterozygous state in multiple symptomatic and asymptomatic individuals diagnosed with primary carnitine deficiency (Amat di San Filippo, 2006; Li, 2010; Lee, 2010; Rose, 2012; Li, 2021; Ambrose, 2022; Martín-Rivada, 2022). This alteration has been identified as co-occurring with the pathogenic alteration SLC22A5 NM_003060 p.R254* c.760C>T in one individual, however, phase (cis or trans) was not confirmed (Li, 2021). This amino acid position is highly conserved in available vertebrate species. The p.R282Q alteration significantly reduces carnitine transport (Rose, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

The SLC22A5 c.845G>A variant is predicted to result in the amino acid substitution p.Arg282Gln. This variant has been reported in the homozygous and compound heterozygous states in patients with systemic primary carnitine deficiency (Amat di San Filippo et al. 2006. PubMed ID: 16652335; Frigeni et al. 2017. PubMed ID: 28841266). When the SLC22A5 protein with the p.Arg282Gln substitution was expressed in Chinese hamster ovary (CHO) cells, the residual carnitine transport activity was no more than 10% of control (Amat di San Filippo et al. 2006. PubMed ID: 16652335; Frigeni et al. 2017. PubMed ID: 28841266). This variant is absent from a large population database, indicating it is rare. Taken together, we classify this variant as pathogenic.