Description
Given the lack of evidence to associate a single change in this gene to the associated phenotype (primary carnitine deficiency) the mode of inheritance required to cause disease (autosomal recessive), and unconvincing functional studies, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The SLC22A5 gene is associated with primary carnitine deficiency, which is characterized by progressive infantile-onset cardiomyopathy, weakness, peripheral neuropathy and recurrent hypoglycemic hypoketotic encephalopathy. Newborn screening can detect PCD early and the condition is amenable to L-carnitine supplementation. The variant has been seen in at least 1 case of primary carnitine deficiency and in homozygous form in an unaffected mother of a child with primary carnitine deficiency (not including this patient's family). Since PCD is a metabolic disorder, two loss-of-function variants are required to cause disease. This variant is present in 1 out of 143 individuals with Primary Carnitine Deficiency (Li et al 2010). Specifically, it was identified in an 18 year old male whose deficiency was detected via newborn screen. He did not have another variant in SLC22A5. In terms of functional data, most variants in SLC22A5 found in symptomatic patients (presumed disease-causing) are located in the first exon. The N-terminus region is very important for protein trafficking from the endoplasmic reticulum to the cell membrane (Maekawa, et al., 2007; Urban, et al., 2006). This variant is not present in this region. Instead it is present in the inter-transmembrane loop. This variant has been reported in homozygous form in an asymptomatic mother of a child who were picked up on newborn screen with primary carnitine deficiency (Schimmenti et al 2007). However, her child has not had an episode. She had an echocardiogram, which was normal. Furthermore, per a study by Amat di San Filippo and colleagues (2006), the R488C variant on its own did not significantly reduce carnitine transport. However, when placed in combination with another variant (A142S), carnitine transport was impaired. These two studies indicate that R488C might not contribute much to impairing function. However, another variant at this codon, p.Arg488His is classified as pathogenic by three laboratories in ClinVar. It is common in the general population. This is possible given that primary carnitine deficiency is an autosomal recessive condition. Functional studies indicate that R488H is only pathogenic when present in cis with A142S. Therefore it is not expected to be pathogenic without a second variant present. According to the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies." The arginine at codon 488 is moderately conserved across species. The variant was reported online in 10 of 123,104 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 16,789 individuals of Latino descent (highest MAF=0.012%), 5 of 55,832 individuals of European descent and 1 of 15,391 individuals of South Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
