ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.364G>T (p.Asp122Tyr)

gnomAD frequency: 0.00043  dbSNP: rs201082652
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000186160 SCV000224396 pathogenic not provided 2017-04-25 criteria provided, single submitter clinical testing
GeneDx RCV000186160 SCV000239186 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing The D122Y pathogenic variant in the SLC22A5 gene has been previously reported in an individual who presented with cardiomyopathy and myopathy, in whom a second SLC22A5 variant was not identified, and serum carnitine concentrations were not reported (Li et al., 2010). Functional studies of the D122Y variant found that it resulted in significantly decreased carnitine transport and decreased expression of human organic cation/carnitine transporter 2 in the plasma membrane of transfected cells (Toh el al., 2011). The D122Y variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. The D122Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D122Y as a pathogenic variant.
Invitae RCV000022318 SCV000632547 pathogenic Renal carnitine transport defect 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 122 of the SLC22A5 protein (p.Asp122Tyr). This variant is present in population databases (rs201082652, gnomAD 0.06%). This missense change has been observed in individual(s) with primary carnitine deficiency, or plasma carnitine deficiency (PMID: 20574985; Invitae). 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: 25371). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 21864509). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000613614 SCV000712504 uncertain significance not specified 2016-11-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp122Tyr variant in SLC22A5 has been reported in the heterozygous state in 2 individuals with suspected primary carnitine deficiency: a 19 y/o female with cardiomyopath y/myopathy (Li 2010;), and an infant who had an abnormal newborn screen with hyp otonia and low plasma carnitine (ARUP db: http://www.arup.utah.edu/database/octn 2/OCTN2_display.php). However, a second variant in SLC22A5 was not detected in e ither individual. The p.Asp122Tyr variant has also been identified in 0.1% (10/1 3986) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs201082652); however this frequency is not hi gh enough to rule out a pathogenic role. Functional studies in cellular models ( Toh 2011), as well as computational prediction and conservation tools, provide s ome evidence that the variant may impact protein function. However, these types of functional data are not sufficient to determine pathogenicity. In summary, wh ile there is some suspicion for a pathogenic role, the clinical significance of the p.Asp122Tyr variant is uncertain due to the absence of a second pathogenic v ariant in SLC22A5 in affected individuals and limited functional data.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000022318 SCV000886116 likely pathogenic Renal carnitine transport defect 2020-04-10 criteria provided, single submitter clinical testing The SLC22A5 c.364G>T; p.Asp122Tyr variant (rs201082652) has been reported in an individual with myopathy, but its clinical significance was not determined (Li 2010). It has also been found heterozygously in an individual tested at ARUP Laboratories with low plasma carnitine levels and transporter activity (in fibroblast) at approximately 53 percent of wildtype (ARUP PCD database). Functional characterization in HEK293 cells indicate that the variant protein shows reduced carnitine transport activity (<10 percent of wildtype) and absence of the protein at the plasma membrane, likely due to the accumulation of the variant protein in the endoplasmic reticulum and Golgi (Toh 2011). The p.Asp122Tyr variant is reported in ClinVar (Variation ID: 25371), and found in the general population with an overall allele frequency of 0.039% (106/271794 alleles) in the Genome Aggregation Database. The aspartic acid at residue 122 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: ARUP PCD database: http://www.arup.utah.edu/database/OCTN2/OCTN2_display.php Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010; 31(8):E1632-51. Toh D et al. Functional analysis of pharmacogenetic variants of human organic cation/carnitine transporter 2 (hOCTN2) identified in Singaporean populations. Biochem Pharmacol. 2011; 82(11):1692-9.
Baylor Genetics RCV000022318 SCV001162975 pathogenic Renal carnitine transport defect 2023-07-18 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital RCV000022318 SCV001423613 likely pathogenic Renal carnitine transport defect 2018-10-09 criteria provided, single submitter clinical testing [ACMG/AMP: PS3, PM2, PM3, PP3] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is predicted to be damaging by multiple functional prediction tools [PP3].
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000186160 SCV001446948 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814008 SCV001755409 likely pathogenic Abnormality of the nervous system 2021-07-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000022318 SCV002022598 likely pathogenic Renal carnitine transport defect 2022-09-27 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000022318 SCV002055741 likely pathogenic Renal carnitine transport defect 2021-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022318 SCV002556148 pathogenic Renal carnitine transport defect 2022-06-24 criteria provided, single submitter clinical testing Variant summary: SLC22A5 c.364G>T (p.Asp122Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 240408 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.0046), allowing no conclusion about variant significance. c.364G>T has been reported in the literature in heterozygous state in multiple individuals, mostly as a biochemical phenotype (e.g. Li_2010, Adhikari_2020, Navarrete_2019, Hou_2020) and in at least one compound heterozygote (who carried a pathogenic variant on the opposite allele) who was reported to be affected with Systemic Primary Carnitine Deficiency (Miller_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated markedly impaired transport function for the variant protein in HEK-293 cells (Toh_2011). Eleven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=4) / likely pathogenic (n=5) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Giacomini Lab, University of California, San Francisco RCV000022318 SCV002576667 uncertain significance Renal carnitine transport defect 2022-10-03 criteria provided, single submitter research
Counsyl RCV000022318 SCV001132488 uncertain significance Renal carnitine transport defect 2018-12-15 no assertion criteria provided clinical testing

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