ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.1463G>A (p.Arg488His)

gnomAD frequency: 0.00347  dbSNP: rs28383481
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000426334 SCV000111946 pathogenic not provided 2015-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000426334 SCV000514640 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing The A142S and R488H variants in the SLC22A5 gene have been reported previously in association with systemic primary carnitine deficiency (CDSP) in patients who harbored A142S and R488H on the same SLC22A5 allele (in cis) with a third variant on the opposite allele (Amat di San Filippo et al., 2006, SLC22A5 Mutation database, www.arup.utah.edu; Mazzini et al. 2011). While the A142S variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the R488H variant was observed with a frequency of 0.5%, 45/8600 alleles, in individuals of European American ancestry. When A142S and R488H were expressed individually in CHO cells, neither variant reduced carnitine transport (Amat di San Filippo et al., 2006). However, when A142S and R488H were present on the same allele, expression in CHO cells showed significantly impaired carnitine transport, indicating that A142S and R488H need to be present on the same SLC22A5 allele in order to impair function (Amat di San Filippo et al., 2006). Therefore when the R488H missense change is present without a second variant on the same SLC22A5 allele, it is not expected to be a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000022386 SCV000584115 pathogenic Renal carnitine transport defect 2013-10-21 criteria provided, single submitter research
Invitae RCV000022386 SCV000632535 likely benign Renal carnitine transport defect 2024-01-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000022386 SCV000886114 benign Renal carnitine transport defect 2021-10-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826038 SCV000967529 uncertain significance not specified 2018-09-17 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg488His var iant in SLC22A5 has been reported in the compound heterozgous state in at least 5 individuals with primary carnitine deficiency (di San Filippo 2006, Mazzini 20 11, Rose 2012, Frigeni 2017, Thompson 2018); however in all of these individuals a second variant (p.Ala142Ser) was identified on the same copy of the SLC22A5 g ene (in cis). Functional studies indicate that p.Arg488His does not significantl y impact carnitine transport alone, and must occur in cis with p.Ala142Ser to im pact protein function (di San Filippo 2006). However, these types of assays may not accurately represent biological function. The p.Arg488His variant has been i dentified in 0.47% (598/126640) of European chromosomes and 0.32% (884/277154) o f total chromosomes by the Genome Aggregation Database, including 6 homozygotes (gnomAD, http://gnomad.broadinstitute.org). It is also present in ClinVar with c onfliciting interpretations of pathogenicity (Variation ID# 38794). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact the protein. Finally, another variant at the same position ( p.Arg488Cys) has been identified in the homozygous state in one individual with primary carnitine deficiency (Schimmenti 2007). In summary, while the clinical s ignificance of this variant is uncertain, these data suggest that, in the absenc e of p.Ala142Ser, the p.Arg488His variant is unlikely to be disease causing. AMC G/AMP criteria applied: PS4_Supporting.
Mendelics RCV000022386 SCV001136973 likely pathogenic Renal carnitine transport defect 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000022386 SCV001313204 uncertain significance Renal carnitine transport defect 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Pars Genome Lab RCV000022386 SCV001736802 uncertain significance Renal carnitine transport defect 2021-05-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000426334 SCV001748129 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing SLC22A5: BS2
Genome-Nilou Lab RCV000022386 SCV001806543 uncertain significance Renal carnitine transport defect 2021-07-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000826038 SCV001983565 likely benign not specified 2023-03-16 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.1463G>A (p.Arg488His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251442 control chromosomes, predominantly at a frequency of 0.0048 within the Latino subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1463G>A has been reported to be in cis with c.424G>T (pathogenic) in the literature in at least one individual affected with Systemic Primary Carnitine Deficiency (e.g. Amat di San Filippo_2006). The variant has been reported in at least one patient with Hypoketotic hypoglycemia and Abnormality of carnitine metabolism, in trans with a VUS (Barbosa-Gouveia_2021). In addition, c.1463G>A in isolation has been reported in general population and is not in linkage disequilibrium with c.424G>T (gnomAD database, Toh_2010). Two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of wild type Carnitine transport activity (Amat di San Filippo_2006, Frigeni_2017). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=3, VUS n=9, benign/likely benign n=3). Based on the evidence outlined above, the variant in isolation was classified as likely benign.
Giacomini Lab, University of California, San Francisco RCV000022386 SCV002576609 uncertain significance Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Centogene AG - the Rare Disease Company RCV000022386 SCV002598529 uncertain significance Renal carnitine transport defect 2017-07-21 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000022386 SCV003823358 uncertain significance Renal carnitine transport defect 2021-11-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000022386 SCV003835636 uncertain significance Renal carnitine transport defect 2023-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000022386 SCV001132485 uncertain significance Renal carnitine transport defect 2017-09-22 no assertion criteria provided clinical testing

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