Reported in patients with an abnormal newborn screen for primary carnitine deficiency who did not have a second variant described (Li et al., 2010); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23090741, 10051646, 25087612, 25525159, 15714519, 20574985, 12204000, 10480371, 29636919, 28841266, 23430869, 21922592, 10425211)

The c.844C>T (p.R282*) alteration, located in exon 5 (coding exon 5) of the SLC22A5 gene, consists of a C to T substitution at nucleotide position 844. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 282. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.004% (10/251492) total alleles studied. The highest observed frequency was 0.025% (4/16256) of African alleles. This variant has been identified in the homozygous state and/or in conjunction with other SLC22A5 variant(s) in individual(s) with features consistent with systemic primary carnitine deficiency (Vaz, 1999; Wang, 1999; Frigeni, 2017; Lin, 2021). In an assay testing SLC22A5 function, this variant showed a functionally abnormal result (Frigeni, 2017). Based on the available evidence, this alteration is classified as pathogenic.

The c.844C>T variant in SLC22A5 is a nonsense variant predicted to introduce a stop codon at amino acid 282. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 28841266). Given the available evidence, this variant is classified as Pathogenic.

The SLC22A5 c.844C>T (p.Arg282Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg282Ter variant has been reported in at least seven studies in a total of ten individuals with systemic primary carnitine deficiency, including in three in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state (Burwinkel et al. 1999; Wang et al. 1999; Vaz et al. 1999; Dobrowolski et al. 2005; Li et al. 2010; Kilic et al. 2012; Rose et al. 2012). The mother of one of the heterozygous patients was also a carrier of the variant but was asymptomatic. Control data are not available for the p.Arg282Ter variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. The p.Arg282Ter variant has also been associated with an unconventional splicing defect (Burwinkel et al. 1999). Fibroblasts from one of the homozygous individuals were shown to exhibit absent saturable carnitine transport and 25% of the normal mRNA expression. Functional studies in Chinese hamster ovary cells showed that transfection with the wildtype protein could increase carnitine transport but that expression of the p.Arg282Ter variant protein could not (Wang et al. 1999). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg282Ter variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: SLC22A5 c.844C>T (p.Arg282X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.9e-05 in 121404 control chromosomes (gnomAD). c.844C>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Wang 1999, Burwinkel 1999, Dobrowolski 2005, Rose 2012). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Wang 1999, Frigeni 2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg282*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs121908886, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 10051646, 10425211, 10480371, 21922592). ClinVar contains an entry for this variant (Variation ID: 6416). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The SLC22A5 c.844C>T variant is predicted to result in premature protein termination (p.Arg282*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with systemic primary carnitine deficiency (see, for example, Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371; Frigeni et al. 2017. PubMed ID: 28841266; Lamhonwah et al. 2018. PubMed ID: 29636919; Lin et al. 2021. PubMed ID: 34863234). In vitro functional studies demonstrate that this variant results in a loss of protein expression and carnitine transport activity (Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. Nonsense variants in SLC22A5 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.

This variant creates a premature translational stop signal (p.Arg282*) and was detected in a proband affected by Systemic Primary Carnitine Deficiency in a compound heterozygous state.ClinVar contains an entry for this variant (Variation ID: 6416).All laboratories classified the variant as pathogenic.