Submissions for variant NM_003060.4(SLC22A5):c.1451G>T (p.Gly484Val)

gnomAD frequency: 0.00039  dbSNP: rs28383480

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186146	SCV000239172	uncertain significance	not provided	2024-10-17	criteria provided, single submitter	clinical testing	Reported previously in an individual with primary carnitine deficiency who had no second SLC22A5 variant (PMID: 28841266) and reported as a variant identified from exome sequencing analysis, however no additional information was provided (PMID: 26633542); Published functional studies demonstrate no damaging effect (PMID: 36343260); 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: 26828774, 18673259, 26633542, 28841266, 34426522, 36343260)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549976	SCV000632533	uncertain significance	Renal carnitine transport defect	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 484 of the SLC22A5 protein (p.Gly484Val). This variant is present in population databases (rs28383480, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 26828774). ClinVar contains an entry for this variant (Variation ID: 203931). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000549976	SCV000782766	uncertain significance	Renal carnitine transport defect	2018-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000549976	SCV001313203	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.
CeGaT Center for Human Genetics Tuebingen	RCV000186146	SCV001501953	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SLC22A5: PP4:Strong, PM2, PM3:Supporting
Genome-Nilou Lab	RCV000549976	SCV002055860	uncertain significance	Renal carnitine transport defect	2021-07-15	criteria provided, single submitter	clinical testing
Giacomini Lab, University of California, San Francisco	RCV000549976	SCV002576628	uncertain significance	Renal carnitine transport defect	2022-10-03	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307436	SCV002600812	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.1451G>T (p.Gly484Val) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00046 in 251436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00046 vs 0.0046), allowing no conclusion about variant significance. c.1451G>T has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Longo_2016, Frigeni_2017), "Abnormality of metabolism/homeostasis" (Retterer_2016), and Sudden Infant Death Syndrome (Neubauer_2017). These reports do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 26633542, 26828774, 28074886, 28841266, 36343260). ClinVar contains an entry for this variant (Variation ID: 203931). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, Polish Academy of Sciences	RCV000785735	SCV000891441	uncertain significance	High myopia	2018-12-17	no assertion criteria provided	research
Natera, Inc.	RCV000549976	SCV001452785	uncertain significance	Renal carnitine transport defect	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000549976	SCV004228905	not provided	Renal carnitine transport defect		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-29-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004754341	SCV005344906	uncertain significance	SLC22A5-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The SLC22A5 c.1451G>T variant is predicted to result in the amino acid substitution p.Gly484Val. This variant was reported in an individual with primary carnitine deficiency and another individual with an abnormality of metabolism/homeostasis; however, no additional segregation or functional evidence was provided (Longo et al. 2016. PubMed ID: 26828774; Retterer et al. 2016. PubMed ID: 26633542). This variant was also reported in a large Turkish sequencing project (Reported as c.1523G>T (p.Gly508Val) in Dataset 4 in Kars et al. 2021. PubMed ID: 34426522). This variant is reported in 0.12% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131729368-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.