chr5-132370336-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_003060.4(SLC22A5):c.364G>T(p.Asp122Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000642 in 1,612,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D122E) has been classified as Uncertain significance.
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.364G>T | p.Asp122Tyr | missense_variant | 1/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.364G>T | p.Asp122Tyr | missense_variant | 1/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000379 AC: 91AN: 240408Hom.: 0 AF XY: 0.000442 AC XY: 58AN XY: 131324
GnomAD4 exome AF: 0.000667 AC: 974AN: 1459912Hom.: 1 Cov.: 34 AF XY: 0.000683 AC XY: 496AN XY: 726144
GnomAD4 genome ? AF: 0.000400 AC: 61AN: 152364Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74510
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:7Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 27, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Oct 09, 2018 | [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]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 10, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Dec 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 03, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 18, 2023 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 25, 2017 | - - |
Abnormality of the nervous system Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2016 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at