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

gnomAD frequency: 0.00347  dbSNP: rs28383481

Total submissions: 18

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-08-15	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 0.0046 in 1614104 control chromosomes, predominantly at a frequency of 0.0055 within the Latino subpopulation in the gnomAD database, including 21 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046). 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). The following publications have been ascertained in the context of this evaluation (PMID: 34440436, 21126579, 28841266, 20208395). ClinVar contains an entry for this variant (Variation ID: 38794). Based on the evidence outlined above, the variant 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
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000022386	SCV005051965	likely pathogenic	Renal carnitine transport defect	2024-02-01	criteria provided, single submitter	curation
Counsyl	RCV000022386	SCV001132485	uncertain significance	Renal carnitine transport defect	2017-09-22	no assertion criteria provided	clinical testing