SLC6A19

protein-coding

solute carrier family 6 member 19, the group of Solute carrier family 6

Gene summary

This gene encodes a system B(0) transmembrane protein that actively transports most neutral amino acids across the apical membrane of epithelial cells. Mutations in this gene may result in Hartnup disorder, an inherited disease with symptoms such as pellagra, cerebellar ataxia, and psychosis. The expression and function of B0AT1 (SLC6A19) in intestinal cells depends on the presence of the accessory protein angiotensin-converting enzyme 2 (ACE2) which, among other functions, acts as a chaperone for membrane trafficking of B0AT1. The ACE2 is also the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and for SARS-CoV-2 that is causing the coronavirus 2019 (COVID-19) pandemic [provided by RefSeq, Jul 2020]

MANE transcript

NM_001003841.3

Inheritance

AR, AD

ClinVar variants

P:52U:250B:163

Top phenotype

Hartnup disease

gnomAD constraint

pLI —, LoF o/e 1.07

Max pathogenic AF

—

Genomic locus

chr5:1,201,595-1,225,111

External References & Databases

Ensembl (ENSG00000174358)

Transcript & Mutation Effects

hg38 • Region Span ~23.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hartnup diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: G2P

hyperglycinuriaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007677

Submitter: PanelApp Australia

Hartnup diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: ClinGen

SLC6A19, which encodes the amino acid transporter B0AT1, was first reported in relation to autosomal recessive Hartnup disease in 2004 (Kleta et al, PMID: 15286787 AND Seow et al, PMID: 15286788). At least 19 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The first proband with this disorder was reported by Baron et al in 1956 (PMID: 13358233). This case report established neutral hyperaminoaciduria as the primary phenotype observed, with others such as skin rash, developmental delay, difficulty walking, and muscle atrophy also arising in some with null B0AT1 transport activity. Since that publication and genetic characterization in Kleta et al, variants in this gene have been reported in at least 19 more probands mostly of European or Asian ancestry (PMIDs: 15286787, 15286788, 18484095). Variants in this gene segregated with disease in about 10 additional family members, yielding a total combined LOD score of 6. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with defective amino acid transport causing the characteristic neutral hyperaminoaciduria and limiting the absorption within the kidney and/or small intestine. Of note, this gene has also been potentially implicated in iminoglycinuria and hyperglycinuria in combination with other transporters such as SLC36A2 and SLC6A20. These assertions will be assessed separately. This gene-disease association is also supported by biochemical function data, RNA and protein expression, and a knockout mouse model. SLC6A19's neutral amino acid transport function combined with the near-exclusive expression in the kidney and small intestine provides significant evidence towards the pathogenicity. The knockout mouse model also showed the characteristic neutral hyperaminoaciduria and defective transport, as well as short stature. In summary, SLC6A19 is definitively associated with autosomal recessive Hartnup disease.This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Hartnup diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: Orphanet

Hartnup diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: PanelApp Australia

Hartnup diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: Labcorp Genetics (formerly Invitae)

Hartnup diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009324

Submitter: Natera

Clinical Genomic Database (CGD)

Hartnup diseaseAR

Manifestation: Biochemical; Dermatologic; Neurologic; Renal

Intervention: Biochemical; Dermatologic

Rationale: Medical therapy (nicotinamide) and sun avoidance can be beneficial for pellagra-like findings; Optimal protein-related treatment is unclear

Refs: 13358233; 5647741; 5813128; 5041315; 2582682; 11394870; 15286787; 15286788; 19033659; 19185582; 19335424; 20399395

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC6A19 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 410

Neutral 1 amino acid transport defectTotal: 202

Inborn genetic diseasesTotal: 84

HyperglycinuriaTotal: 55

IminoglycinuriaTotal: 53

not specifiedTotal: 38

SLC6A19-related disorderTotal: 19

High myopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001003841.3. 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			6 clinvar	136 clinvar	5 clinvar	147
missense		15 clinvar	240 clinvar	22 clinvar		277
nonsense	3 clinvar	15 clinvar	2 clinvar			20
start loss			1 clinvar			1
frameshift	6 clinvar	3 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	9 clinvar				10
Total	10	42	250	158	5	465

Highest pathogenic variant AF is 0.003103546

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001003841.3	RefSeq	NP_001003841.1	12	MANE Select
ENST00000304460.11	Ensembl	ENSP00000305302.10	12	MANE Select
ENST00000515652.5	Ensembl	ENSP00000425701.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
Nuclear Receptors Meta-Pathway
NRF2 pathway
Amine compound SLC transporters

Biological Process

amino acid transmembrane transport
neurotransmitter transport
amino acid transport
response to nutrient
neutral amino acid transport

Molecular Function

neurotransmitter:sodium symporter activity
protein binding
amino acid transmembrane transporter activity
neutral amino acid transmembrane transporter activity

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304460
Coding exons: 12
Length: 23523
Individuals with no LoFs: 125542
Homozygous LoFs: 0
Heterozygous LoFs: 205
Defined: 125747
p: 0.000815

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0401	388	386	1.01	0.0000271	4134
Missense (PolyPhen)		163	171.82	0.94868		1852
Synonymous	-1.67	210	181	1.16	0.0000155	1291
Loss of Function	-0.383	35	32.6	1.07	0.00000194	302

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00080	0.00080	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00082	0.00082	rare
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00065	0.00065	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells. This uptake is sodium-dependent and chloride- independent. {ECO:0000269|PubMed:15286788}.;
Disease: DISEASE: Hyperglycinuria (HG) [MIM:138500]: A condition characterized by excess of glycine in the urine. In some cases it is associated with renal colic and renal oxalate stones. {ECO:0000269|PubMed:19033659}. Note=The disease may be caused by mutations affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for hyperglycinuria.; DISEASE: Iminoglycinuria (IG) [MIM:242600]: A disorder of renal tubular reabsorption of glycine and imino acids (proline and hydroxyproline), marked by excessive levels of all three substances in the urine. {ECO:0000269|PubMed:19033659}. Note=The disease may be caused by mutations affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for iminoglycinuria. Additional polymorphisms and mutations in SLC6A18 can contribute to the IG phenotype in some families.;

Recessive Scores

pRec: 0.165

Intolerance Scores

LoFtool: 0.687
RVIS EVS: -1.92
RVIS percentile EVS: 1.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.202

Gene Damage Prediction

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