chr5-132370108-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_003060.4(SLC22A5):c.136C>T(p.Pro46Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,611,858 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00047 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00079 ( 1 hom. )
Consequence
SLC22A5
NM_003060.4 missense
NM_003060.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.28
Genes affected
SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 5-132370108-C-T is Pathogenic according to our data. Variant chr5-132370108-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132370108-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-132370108-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SLC22A5 | NM_003060.4 | c.136C>T | p.Pro46Ser | missense_variant | 1/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SLC22A5 | ENST00000245407.8 | c.136C>T | p.Pro46Ser | missense_variant | 1/10 | 1 | NM_003060.4 | ENSP00000245407.3 |
Frequencies
GnomAD3 genomes 0.000473 AC: 72AN: 152214Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000446 AC: 109AN: 244204Hom.: 0 AF XY: 0.000413 AC XY: 55AN XY: 133208
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GnomAD4 exome AF: 0.000791 AC: 1154AN: 1459644Hom.: 1 Cov.: 31 AF XY: 0.000724 AC XY: 526AN XY: 726162
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GnomAD4 genome 0.000473 AC: 72AN: 152214Hom.: 1 Cov.: 33 AF XY: 0.000511 AC XY: 38AN XY: 74376
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal carnitine transport defect Pathogenic:15
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2017 | Variant summary: The SLC22A5 c.136C>T (p.Pro46Ser) variant located in an extracellular loop close to putative glycosylation sites (Filippo_2011) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. These in silico predictions are confirmed via multiple functional studies, Rose_2012 and Filipp_2011, that indicate the variant to "impair glycosylation and maturation of OCTN2 transporters to the plasma membrane." The variant of interest was observed in 55/99736 control chromosomes at a frequency of 0.0005515, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC22A5 variant (0.0045644). Multiple publications have cited the variant in both asymptomatic mothers and symptomatic patients, although indicated to have a mild phenotype (easy fatigability, muscle pain with exercise, fasting tolerance). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the SLC22A5 protein (p.Pro46Ser). This variant is present in population databases (rs202088921, gnomAD 0.08%). This missense change has been observed in individuals with primary carnitine deficiency (PMID: 17126586, 20027113, 20574985, 23430798, 23430858, 23963628). ClinVar contains an entry for this variant (Variation ID: 193250). 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: 17126586, 21126579). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 17, 2019 | NM_003060.3(SLC22A5):c.136C>T(P46S) is classified as likely pathogenic in the context of primary carnitine deficiency and may be associated with a mild form of this disease. Sources cited for classification include the following: PMID 17126586, 21126579, 20574985, 21922592, 23430798 and 23653224. Classification of NM_003060.3(SLC22A5):c.136C>T(P46S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 03, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 05, 2021 | The SLC22A5 c.136C>T; p.Pro46Ser variant (rs202088921) is reported in the literature in a homozygous or compound heterozygous state in multiple individuals with primary carnitine deficiency (de Boer 2013, Filippo 2011, Frigeni 2017, Rasmussen 2014, Schimmenti 2007). Functional analyses of the variant protein show reduced transport to the cell membrane and substantially reduced carnitine transport activity (Filippo 2011, Frigeni 2017, Rose 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 193250), and it is found in the general population at a frequency of 0.04% (118/275568 alleles) in the Genome Aggregation Database. The proline at codon 46 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.899). Based on available information, this variant is considered to be pathogenic. References: de Boer L et al. Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency. JIMD Rep. 2013;10:39-40. Filippo CA et al. Glycosylation of the OCTN2 carnitine transporter: study of natural mutations identified in patients with primary carnitine deficiency. Biochim Biophys Acta. 2011 Mar;1812(3):312-20. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. Rasmussen J et al. Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency. MGM Reports. 2014 Apr; 1:241-248. Rose EC et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Schimmenti LA et al. Expanded newborn screening identifies maternal primary carnitine deficiency. Mol Genet Metab. 2007 Apr;90(4):441-5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Feb 02, 2024 | ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 22, 2018 | Across a selection of the available literature, the SLC22A5 c.136C>T (p.Pro46Ser) missense variant has been reported in a total of 33 individuals with systemic primary carnitine deficiency, including in a homozygous state in two, in a compound heterozygous state in 25, and in a heterozygous state in six (Li et al. 2010; Filippo et al. 2011; Rose et al. 2012; De Biase et al. 2012; de Boer et al. 2013; Rasmussen et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00093 in the European (non-Finnish) population of the Exome Aggregation Consortium. When expressed in CHO cells, the p.Pro46Ser variant protein had reduced carnitine transport compared to wild type and was largely retained in the cytoplasm rather than being found at the plasma membrane (Filippo et al. 2011). Consistent with the residual transport activity, the variant appears to be associated with a milder phenotype and is commonly found in asymptomatic individuals; at least 11 of the 25 compound heterozygous probands reported here were asymptomatic. Based on the collective evidence, the p.Pro46Ser variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 06, 2016 | The p.Pro46Ser variant in SLC22A5 has been reported in at least 10 individuals w ith primary carnitine deficiency in the compound heterozygous state (Schimmenti 2007, di San Filippo 2011, Rasmussen 2014). The phenotypic spectrum ranges from easy fatigability, cardiac arrhythmias, and fasting intolerance to asymptomatic adults. This variant has also been identified 0.05% (55/99,736) of chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202088921). In vitro functional studies also provide evidence that the p.Pro4 6Ser variant may impact protein function (di San Filippo 2011). In summary, this variant meets our criteria to be classified as pathogenic for primary carnitine deficiency in an autosomal recessive manner based upon its identification in tr ans with other disease-associated variants in patients and functional impact. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary systemic carnitine deficiency (MIM#212140). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variant has been found in asymptomatic or minimally symptomatic adult women and in a compound heterozygous mother with cardiac arrest (PMID: 28841266). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (70 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequent mutations identified in individuals with primary systemic carnitine deficiency (ClinVar, PMID: 17126586, 22989098, 28841266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 22, 2021 | - - |
not provided Pathogenic:9
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 04, 2023 | PP3, PM3, PM5, PS3, PS4_moderate - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 24, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2020 | Carnitine transport was significantly decreased in both skin fibroblasts from patients harboring P46S and in CHO cells overexpressing P46S (Frigeni et al., 2017; Rose et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31980526, 30609409, 21126579, 17126586, 29614331, 29111448, 23430858, 27896095, 26828774, 28711408, 28841266, 23653224, 21922592, 20574985, 20027113, 23520115, 22989098, 23430798, 23963628) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 13, 2021 | ACMG categories: PM1,PM2,PP2,PP3,PP5 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at