ClinVar Miner

Submissions for variant NM_003060.4(SLC22A5):c.364G>T (p.Asp122Tyr) (rs201082652)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 122 of the SLC22A5 protein (p.Asp122Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs201082652, ExAC 0.07%). This variant has been reported in combination with another SLC22A5 variant in individuals affected with primary carnitine deficiency (Invitae). An individual with an abnormal newborn screening result consistent with a low free carnitine or plasma carnitine deficiency was reported to be heterozygous but no other SLC22A5 allele present (PMID: 20574985). ClinVar contains an entry for this variant (Variation ID: 25371). Experimental studies have shown that this missense change causes a markedly impaired transport function of the channel in vitro (PMID: 21864509). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare 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: 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 ://; 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: 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 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
Research and Development, ARUP Laboratories RCV000022318 SCV000043003 not provided Renal carnitine transport defect no assertion provided clinical testing
Counsyl RCV000022318 SCV001132488 uncertain significance Renal carnitine transport defect 2018-12-15 no assertion criteria provided clinical testing

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