SLC22A5

protein-coding

solute carrier family 22 member 5, the group of Solute carrier family 22

Gene summary

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]

Previous symbols:

CDSP

MANE transcript

NM_003060.4

Inheritance

ClinVar variants

P:333U:397B:341

Top phenotype

Carnitine deficiency, systemic primary

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr5:132,369,710-132,395,613

External References & Databases

Ensembl (ENSG00000197375)

Transcript & Mutation Effects

hg38 • Region Span ~25.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic primary carnitine deficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: Labcorp Genetics (formerly Invitae)

short QT syndromeNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0000453

Submitter: ClinGen

SLC22A5 encodes a sodium ion-dependent, high affinity carnitine transporter protein. Genetic variants in this gene cause primary systemic carnitine deficiency, an autosomal recessive disorder. Homozygote or compound heterozygote variants in SLC22A5 have been identified in unexplained SCD or resuscitated cardiac arrest cases with abbreviation of the QT interval and without overt extra-cardiac manifestations (PMIDs 26190315, 31472821). Because the QT interval abbreviation was reversible by oral carnitine supplementation, the Expert Panel viewed this gene as a SQTS-mimic but as a cause of true SQTS classified it as ‘disputed’.

systemic primary carnitine deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: Myriad Women's Health

systemic primary carnitine deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: G2P

systemic primary carnitine deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: ClinGen

*SLC22A5* was first reported in relation to autosomal recessive systemic primary carnitine deficiency disease in 1999 (Nezu et al., PMID:9916797).Thirteen variants (missense, nonsense, frameshift, splice site) that have been reported in 12 probands in six publications (PMIDs: 9916797, 10072434, 10051646, 10425211, 10480371,10679939) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 27896095, 10072434, 10051646, 10480371, 9685390, 9837751, 10679939). In summary, there is definitive evidence supporting the relationship between *SLC22A5* and autosomal recessive systemic primary carnitine deficiency disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Fatty Acid Oxidation Disorders GCEP on April 24th, 2018 (SOP Version 5).

systemic primary carnitine deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: Natera

systemic primary carnitine deficiency diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: Orphanet

systemic primary carnitine deficiency diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: Ambry Genetics

systemic primary carnitine deficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008919

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Carnitine deficiency, systemic primaryAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Biochemical; Pharmacogenomic

Rationale: Early disease recognition with prompt carnitine therapy can be immediately life-saving and beneficial long-term; Certain agents (eg, specific antibiotics) have been reported to precipitate severe reactions, and should be avoided

Refs: 234182; 7432384; 7254270; 7131143; 3974805; 3181209; 3185635; 2235122; 1763895; 2235122; 9826541; 9700603; 11261427; 9634512; 9916797; 11715001; 12210323; 15303004; 16652335; 17126586; 20027113; 20574985; 21922592; 22566287; 22989098; 23379544

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC22A5 variants in ClinVar

14 Conditions Cataloged

Renal carnitine transport defectTotal: 1178

not providedTotal: 208

Carnitine deficiencyTotal: 125

not specifiedTotal: 97

Decreased circulating carnitine concentrationTotal: 84

SLC22A5-related disorderTotal: 74

Inborn genetic diseasesTotal: 53

Inborn errors of metabolismTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003060.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		8 clinvar	306 clinvar	5 clinvar	320
missense	19 clinvar	129 clinvar	385 clinvar	29 clinvar	1 clinvar	563
nonsense	28 clinvar	22 clinvar	2 clinvar			52
start loss	1 clinvar	5 clinvar				6
frameshift	47 clinvar	41 clinvar	1 clinvar			89
splice donor/acceptor (+/-2bp)	12 clinvar	28 clinvar	1 clinvar			41
Total	108	225	397	335	6	1071

Highest pathogenic variant AF is 0.00084423024

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003060.4	RefSeq	NP_003051.1	10	MANE Select
ENST00000245407.8	Ensembl	ENSP00000245407.3	10	MANE Select
NM_001308122.2	RefSeq	NP_001295051.1	11	Standard
ENST00000415928.6	Ensembl	ENSP00000388838.2	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc22a5	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

slc22a5

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Choline metabolism in cancer - Homo sapiens (human)
Metabolism of lipids
Import of palmitoyl-CoA into the mitochondrial matrix
Metabolism
Fatty acid metabolism

Biological Process

sodium ion transport
drug transmembrane transport
quaternary ammonium group transport
carnitine transport
drug transport

Molecular Function

protein binding
ATP binding
carnitine transmembrane transporter activity
drug transmembrane transporter activity
symporter activity

Cellular Component

plasma membrane
integral component of membrane
apical plasma membrane
brush border membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245407
Coding exons: 10
Length: 25863
Individuals with no LoFs: 125643
Homozygous LoFs: 0
Heterozygous LoFs: 105
Defined: 125748
p: 0.000418

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.357	332	314	1.06	0.0000173	3591
Missense (PolyPhen)		79	78.584	1.0053		889
Synonymous	-0.847	144	132	1.09	0.00000752	1180
Loss of Function	0.160	24	24.9	0.965	0.00000135	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0017	0.0017	notable
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00040	0.00039	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3. {ECO:0000269|PubMed:10454528}.;

Recessive Scores

pRec: 0.286

Intolerance Scores

LoFtool: 0.403
RVIS EVS: 0.8
RVIS percentile EVS: 87.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.255

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium