SLC7A9

protein-coding

solute carrier family 7 member 9, the group of Solute carrier family 7

Gene summary

This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. Alternate transcript variants, which encode the same protein, have been found for this gene. [provided by RefSeq, Jul 2011]

Previous symbols:

CSNU3

MANE transcript

NM_014270.5

Inheritance

AR, AD, SD

ClinVar variants

P:102U:165B:80

Top phenotype

Cystinuria

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr19:32,830,509-32,869,767

External References & Databases

Ensembl (ENSG00000021488)

Transcript & Mutation Effects

hg38 • Region Span ~39.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009067

Submitter: Natera

cystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009067

Submitter: ClinGen

SLC7A9 was first reported in relation to autosomal recessive cystinuria in 1999 (Feliubadaló et al., PMID: 10471498). At least 153 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in 5 publications (PMIDs: 23532419, 16609684, 25296721, 11157794, 10471498). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the biochemical function of SLC7A9 in a cystine, ornithine, arginine, and lysine transporter protein complex (PMID: 12234930), its interaction with rBAT in that complex (PMID: 18332091), and its expression in the kidneys (PMID: 25613900), where the protein complex absorbs cystine, ornithine, arginine, and lysine back into the blood during urine formation. This gene-disease relationship is further supported by a knockout mouse model which recapitulates the elevated cystine, ornithine, arginine, and lysine levels associated with abnormal function of this protein, leading to formation of cystine crystals and stones in the bladder or kidneys (PMID: 12915471). In mice, as in humans, the heterozygous individuals have an intermediate level of urinary cystine; elevated above normal but lower than the homozygotes (Reviewd in PMID: 30515543). In humans the cystinuria in heterozygotes has, on occassion, been associated with kidney stones however modifying genes or environmental factors may contribute to the phenotype (PMID: 25383320). In summary, SLC7A9 is definitively associated with autosomal recessive cystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

cystinuriaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009067

Submitter: PanelApp Australia

cystinuria type BSUPPORTIVE

Inheritance Pattern: SD

Disease ID:MONDO:0019746

Submitter: Orphanet

cystinuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009067

Submitter: PanelApp Australia

cystinuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009067

Submitter: Labcorp Genetics (formerly Invitae)

cystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009067

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

cystinuriaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009067

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

CystinuriaAD/AR

Manifestation: Biochemical; Renal

Intervention: Biochemical; Renal

Rationale: Measures to maintain high fluid intake, as well as medical therapy (eg, urine alkalinization, and, in some, penicillamine) can be beneficial

Refs: 5925065; 2502678; 10471498; 11157794; 12239244; 12371955; 12820697; 12820697; 17539912

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC7A9 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 242

CystinuriaTotal: 201

SLC7A9-related disorderTotal: 58

Inborn genetic diseasesTotal: 38

not specifiedTotal: 33

Cystine urolithiasisTotal: 8

Bethlem myopathy 1ATotal: 1

Polycystic kidney disease, adult typeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014270.5. 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	2 clinvar	8 clinvar	69 clinvar	3 clinvar	83
missense	6 clinvar	32 clinvar	153 clinvar	8 clinvar		199
nonsense	5 clinvar	11 clinvar				16
start loss		1 clinvar				1
frameshift	14 clinvar	14 clinvar	2 clinvar			30
splice donor/acceptor (+/-2bp)	5 clinvar	11 clinvar	2 clinvar			18
Total	31	71	165	77	3	347

Highest pathogenic variant AF is 0.0040689

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014270.5	RefSeq	NP_055085.1	12	MANE Select
ENST00000023064.9	Ensembl	ENSP00000023064.3	12	MANE Select
NM_001126335.2	RefSeq	NP_001119807.1	12	Standard
NM_001243036.2	RefSeq	NP_001229965.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Polythiazide Action Pathway
Methyclothiazide Action Pathway
Bumetanide Action Pathway
Spironolactone Action Pathway

Biological Process

amino acid transmembrane transport
neutral amino acid transport
L-cystine transport
leukocyte migration
protein-containing complex assembly

Molecular Function

protein binding
neutral amino acid transmembrane transporter activity
L-amino acid transmembrane transporter activity
L-cystine transmembrane transporter activity
peptide antigen binding

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000023064
Coding exons: 12
Length: 39258
Individuals with no LoFs: 125624
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.805	256	295	0.868	0.0000189	3145
Missense (PolyPhen)		89	115.29	0.77196		1239
Synonymous	0.158	125	127	0.982	0.00000995	998
Loss of Function	1.12	17	22.8	0.747	9.83e-7	279

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00070	0.00070	rare
South Asian	0.00036	0.00036	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the high-affinity, sodium-independent transport of cystine and neutral and dibasic amino acids (system b(0,+)-like activity). Thought to be responsible for the high- affinity reabsorption of cystine in the kidney tubule. {ECO:0000269|PubMed:10471498, ECO:0000269|PubMed:10588648, ECO:0000269|PubMed:16609684}.;

Recessive Scores

pRec: 0.273

Intolerance Scores

LoFtool: 0.194
RVIS EVS: -0.53
RVIS percentile EVS: 20.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.148

Gene Damage Prediction

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