SLC36A2

protein-coding

solute carrier family 36 member 2, the group of Solute carrier family 36

Gene summary

This gene encodes a pH-dependent proton-coupled amino acid transporter that belongs to the amino acid auxin permease 1 protein family. The encoded protein primarily transports small amino acids such as glycine, alanine and proline. Mutations in this gene are associated with iminoglycinuria and hyperglycinuria. [provided by RefSeq, Sep 2010]

MANE transcript

NM_181776.3

Inheritance

AR, AD, SD, Digenic

ClinVar variants

U:104B:56

Top phenotype

Hyperglycinuria; Iminoglycinuria; Iminoglycinuria, digenic

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr5:151,314,972-151,347,590

External References & Databases

Ensembl (ENSG00000186335)

Transcript & Mutation Effects

hg38 • Region Span ~32.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperglycinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0007677

Submitter: PanelApp Australia

iminoglycinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009448

Submitter: ClinGen

The relationship between SLC36A2 and iminoglycinuria was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2024. Iminoglycinuria is defined as excess urinary excretion of proline, hydroxyproline, and glycine, and is thought to be benign. Variants in SLC36A2 were first reported in individuals with iminoglycinuria in 2008 (Broer et al, PMID 19033659). The authors report one family in which a child who is homozygous for a canonical splice site variant has iminoglycinuria. Two siblings and both parents were heterozygous for the variant and have hyperglycinuria. In a further four families, individuals with iminoglycinuria were reported to be homozygous for a missense variant (p.Gly87Val, resulting in 50% normal transport activity) in SLC36A2 and heterozygous for a missense variant in another gene, SLC6A20 (families 1-3), or homozygous for an intronic variant affecting branch point selection in SLCA19 (family 4). One individual who is homozygous for p.Gly87Val in SLC36A2 without additional changes in SLC6A20 or SLC6A19 was reported to have hyperglycinuria but normal urinary proline and hydroxyproline levels. Thus it appears that for less severe variants in SLC36A2, the contribution of variants in other genes involved in amino acid transport may be required for iminoglycinuria. Another individual has been reported who is homozygous for a nonsense variant in SLC36A2 (PMID 26141664). This individual has multiple congenital anomalies, most likely not caused by the SLC36A2 variant. No details are available regarding the urine proline, hydroxyproline, and glycine levels for this patient. This gene-disease relationship is supported by the function of SLC36A2 (also known as PAT2) as a high affinity transporter of proline and glycine (Boll et al, 2002, PMID 11959859; Boll et al, 2003, PMID 12809675), and expression of SLC36A2 in the kidney (https://gtexportal.org/home/gene/SLC36A2, PMID 25954001). In summary, there is limited evidence to support the relationship between SLC36A2 and iminoglycinuria. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was originally approved by the Aminoacidopathy Gene Curation Expert Panel on March 13, 2020. This gene-disease relationship was re-evaluated on March 7, 2024. As a result of this re-evaluation, the classification did not change.

iminoglycinuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009448

Submitter: Orphanet

hyperglycinuriaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007677

Submitter: Labcorp Genetics (formerly Invitae)

iminoglycinuriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009448

Submitter: Labcorp Genetics (formerly Invitae)

hyperglycinuriaLIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0007677

Submitter: Ambry Genetics

iminoglycinuriaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009448

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hyperglycinuria; Iminoglycinuria; Iminoglycinuria, digenicAD/AR/Digenic

Manifestation: Biochemical; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Variants in other genes (eg, SLC6A18, SLC6A19, SLC6A20) may affect manifestations

Refs: 19033659

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC36A2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 122

not specifiedTotal: 73

HyperglycinuriaTotal: 16

IminoglycinuriaTotal: 15

SLC36A2-related disorderTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181776.3. 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			2 clinvar	29 clinvar	6 clinvar	37
missense			92 clinvar	19 clinvar	1 clinvar	112
nonsense			1 clinvar	1 clinvar		2
start loss						0
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	104	49	7	160

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181776.3	RefSeq	NP_861441.2	10	MANE Select
ENST00000335244.9	Ensembl	ENSP00000334223.4	10	MANE Select
ENST00000518280.5	Ensembl	ENSP00000428453.1	5	Standard
ENST00000518617.5	Ensembl	ENSP00000430149.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Amino acid transport across the plasma membrane
Amino acid and oligopeptide SLC transporters
Transport of inorganic cations/anions and amino acids/oligopeptides
SLC-mediated transmembrane transport
Transport of small molecules

Biological Process

amino acid transmembrane transport
ion transport
amino acid transport
L-alanine transport
glycine transport

Molecular Function

amino acid:proton symporter activity
proton transmembrane transporter activity
amino acid transmembrane transporter activity
L-alanine transmembrane transporter activity
glycine transmembrane transporter activity

Cellular Component

cytoplasm
plasma membrane
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335244
Coding exons: 10
Length: 32613
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0784	270	274	0.987	0.0000162	3140
Missense (PolyPhen)		87	79.792	1.0903		976
Synonymous	0.466	104	110	0.944	0.00000660	1005
Loss of Function	0.684	16	19.2	0.832	9.95e-7	227

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00081	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.00029	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in a pH-dependent electrogenic neuronal transport and sequestration of small amino acids. Transports glycine and proline. Inhibited by sarcosine (By similarity). {ECO:0000250, ECO:0000269|PubMed:19033659}.;
Disease: 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 is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Mutations in SLC36A2 that retain residual transport activity result in the IG phenotype only when combined with haploinsufficiency of the imino acid transporter SLC6A20 or deficiency of the neutral amino acid transporter SLC6A19. Additional polymorphisms and mutations in SLC6A18 can contribute to iminoglycinuria in some families.;

Recessive Scores

pRec: 0.0970

Intolerance Scores

LoFtool: 0.912
RVIS EVS: 0.05
RVIS percentile EVS: 57.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0689

Gene Damage Prediction

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