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

gnomAD frequency: 0.00043  dbSNP: rs201082652

Total submissions: 17

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	uncertain significance	not provided	2024-12-18	criteria provided, single submitter	clinical testing	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 (PMID: 21864509); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31980526, 32371413, 27956261, 27320645, 28074886, 30626930, 34426522, 21864509, 32778825, 20208395, 35281663, 20574985, 29659532, 38374194, 36343260, 37510298)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022318	SCV000632547	pathogenic	Renal carnitine transport defect	2025-02-02	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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	2024-03-29	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	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	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: SLC22A5 c.364G>T (p.Asp122Tyr) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of 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, Lindholm_2021) and in at least three compound heterozygotes (who all carried a second pathogenic/likely pathogenic SLC22A5 variant) affected with Systemic Primary Carnitine Deficiency (e.g., Miller_2020, Ambrose_2022, Martin-Rivada_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated markedly impaired transport function for the variant protein (e.g., Toh_2011, Koleske_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 36109795, 31980526, 37510298, 36343260, 20574985, 34802252, 35281663, 32371413, 30626930, 21864509, 20208395). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 5; likely pathogenic, n = 5; VUS, n = 3). 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
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000022318	SCV005051963	pathogenic	Renal carnitine transport defect	2024-02-01	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000186160	SCV005413698	pathogenic	not provided	2024-04-17	criteria provided, single submitter	clinical testing	PP3, PM3_strong, PS3
Fulgent Genetics, Fulgent Genetics	RCV000022318	SCV005669189	likely pathogenic	Renal carnitine transport defect	2024-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000022318	SCV001132488	uncertain significance	Renal carnitine transport defect	2018-12-15	no assertion criteria provided	clinical testing