Submissions for variant NM_003060.4(SLC22A5):c.1462C>T (p.Arg488Cys)

gnomAD frequency: 0.00005  dbSNP: rs377216516

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528265	SCV000632534	pathogenic	Renal carnitine transport defect	2025-01-27	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 488 of the SLC22A5 protein (p.Arg488Cys). This variant is present in population databases (rs377216516, gnomAD 0.01%). This missense change has been observed in individual(s) with primary carnitine deficiency with low levels of plasma free carnitine (PMID: 17126586, 30863740). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 460399). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC22A5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000786403	SCV001773209	pathogenic	not provided	2020-12-09	criteria provided, single submitter	clinical testing	Expression studies found that R488C results in OCTN2 carnitine transporter activity that is approximately 9.5% that of wild-type (Frigeni et al. 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28841266, 17126586, 20574985, 25087612, 30863740)
Genome-Nilou Lab	RCV000528265	SCV002055834	pathogenic	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000528265	SCV002810403	likely pathogenic	Renal carnitine transport defect	2022-02-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000528265	SCV004201249	likely pathogenic	Renal carnitine transport defect	2024-03-27	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000528265	SCV005051967	pathogenic	Renal carnitine transport defect	2024-02-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000528265	SCV005185696	pathogenic	Renal carnitine transport defect	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1462C>T (p.Arg488Cys) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251444 control chromosomes. c.1462C>T has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (example, Adhikari_2020, Frigeni_2017, Schimmenti_2007, Zhou_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in CHO cells (Frigeni_HM_2017). The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 28841266, 17126586, 30863740). ClinVar contains an entry for this variant (Variation ID: 460399). Based on the evidence outlined above, the variant was classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786403	SCV000925218	uncertain significance	not provided	2017-04-11	no assertion criteria provided	provider interpretation	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.