ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.1324_1325delinsAT (p.Ala442Ile)

dbSNP: rs267607053
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186157 SCV000239183 pathogenic not provided 2020-08-14 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect based on significantly reduced carnitine transport (Rose et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21922592, 20027113, 20574985, 28841266)
Labcorp Genetics (formerly Invitae), Labcorp RCV000006797 SCV000632521 pathogenic Renal carnitine transport defect 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 442 of the SLC22A5 protein (p.Ala442Ile). This variant is present in population databases (rs267607053, gnomAD 0.001%). This missense change has been observed in individual(s) with primary carnitine deficiency and systemic carnitine deficiency (PMID: 20027113, 21922592, 28841266). ClinVar contains an entry for this variant (Variation ID: 6428). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000006797 SCV002055827 pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000006797 SCV002809341 likely pathogenic Renal carnitine transport defect 2022-03-18 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000006797 SCV003821053 pathogenic Renal carnitine transport defect 2022-01-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV000006797 SCV004201304 pathogenic Renal carnitine transport defect 2024-02-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000006797 SCV005203886 pathogenic Renal carnitine transport defect 2024-07-30 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.1324_1325delinsAT (p.Ala442Ile) results in a non-conservative amino acid change in 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 3.8e-05 in 1614054 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (3.8e-05 vs 0.0046), allowing no conclusion about variant significance. c.1324_1325delinsAT has been reported in the literature in the homozygous and compound heterozygous states in individuals affected with Systemic Primary Carnitine Deficiency (e.g. Frigeni_2017, El-Hattab_2010, Ambroze_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant causes reduced carnitine transport activity in vitro and in vivo (e.g. Frigeni_2017). The following publications have been ascertained in the context of this evaluation (PMID: 36109795, 20027113, 28841266). ClinVar contains an entry for this variant (Variation ID: 6428). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000006797 SCV000026993 pathogenic Renal carnitine transport defect 2015-04-29 no assertion criteria provided literature only
Counsyl RCV000006797 SCV001132489 uncertain significance Renal carnitine transport defect 2019-01-24 no assertion criteria provided clinical testing

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