GeneBe

SLC17A5

protein-coding

solute carrier family 17 member 5, the group of Solute carrier family 17

Gene summary

This gene encodes a membrane transporter that exports free sialic acids that have been cleaved off of cell surface lipids and proteins from lysosomes. Mutations in this gene cause sialic acid storage diseases, including infantile sialic acid storage disorder and and Salla disease, an adult form. [provided by RefSeq, Jul 2008]

Previous symbols:
  • SIASD

MANE transcript

NM_012434.5

Inheritance

AR

ClinVar variants

P:174U:190B:185

Top phenotype

Infantile sialic acid storage disorder; Sialuria, Finnish type (Salla disease)

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr6:73,593,379-73,653,992

External References & Databases

Ensembl (ENSG00000119899)NCBI Gene (26503)OMIM (604322)HGNC:10933GenCCUniProt (Q9NRA2)AlphaFoldClinVar (SLC17A5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~60.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

free sialic acid storage disease, infantile formSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010027

Submitter: Orphanet

free sialic acid storage disease, infantile formSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010027

Submitter: Genomics England PanelApp

free sialic acid storage diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019366

Submitter: ClinGen

The relationship between the *SLC17A5* gene and free sialic acid storage disease (free SASD) an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 11, 2022. SLC17A5 encodes solute carrier family 17 member 5 (also known as sialin), a lysosomal membrane transporter protein that exports sialic acid (the majority of which is N-acetylneuraminic acid, Neu5Ac) and other acidic hexoses from lysosomes (PMID: 2010546). Among patients with free sialic acid storage disease, deficient SLC17A5 function results in impaired sialic acid export from lysosomes and lysosomal accumulation of sialic acid (PMID: 15557321), leading to a spectrum of clinical manifestations including urinary excretion of free sialic acid, neurological and developmental symptoms with severity ranging from the milder phenotype, Salla disease (SD), to the most severe phenotype, infantile free sialic acid storage disease (ISSD) (as reviewed in PMID: 20301643, 33862140). Lumping and splitting: Variants in *SLC17A5* have been reported in individuals with Salla disease (MIM# 604369) and Sialic acid storage disorder, infantile (MIM# 269920). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for these conditions. Salla disease and Sialic acis storage disorder, infantile represent a clinical continuum (PMIDs: 20301643, 33862140). Therefore, the two entities have been lumped as free sialic acid storage disease. The disease mechanism for free SASD is loss of function. ISSD was first reported by Tondeur et al. in 1982 (PMID: 7151835); first report of biallelic variants in SLC17A5 among ISSD patients by Verheijen in 1999 (PMID: 10581036). Both case-level (genetic) and experimental evidence support the relationship between SLC17A5 and ISSD. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 15172005, PMID: 23900835, PMID: 15805149, PMID: 10581036). In total, ten variants from seven probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence (4 points total) for the relationship between SLC17A5 and free SASD includes: the biochemical function of the gene product (solute carrier family 17 member 5) being consistent with the clinical and biochemical findings identified in individuals with ISSD (PMID: 2010546, PMID: 15557321, PMID: 33862140; PMID: 10581036) and the biochemical and clinical features of *SLC17A5* knockout mice (PMID: 28189729). In sum, *SLC17A5* is definitively associated with free SASD. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification approved by the ClinGen Lysosomal Diseases Gene Curation Expert Panel, October 30, 2023 (SOP v9). **Data provided by the ClinGen Prenatal GCEP from November 5, 2024 secondary analysis:** There is a clear prenatal/neonatal phenotype associated with SLC17A5 and free sialic acid storage disease, evident in many probands demonstrating the gene-disease association, biochemical function, and animal models. Common prenatal findings include ascites, hydrops fetalis, pericardial/pleural effusions, edema, ventriculomegaly, and hepatomegaly (PMIDs: 15805149, 29654786, 34906519).

free sialic acid storage diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019366

Submitter: Natera

Salla diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011449

Submitter: Genomics England PanelApp

intermediate severe Salla diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017737

Submitter: Orphanet

Salla diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011449

Submitter: Orphanet

free sialic acid storage disease, infantile formSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010027

Submitter: PanelApp Australia

Salla diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011449

Submitter: G2P

Salla diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011449

Submitter: PanelApp Australia

free sialic acid storage disease, infantile formSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010027

Submitter: Labcorp Genetics (formerly Invitae)

Salla diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011449

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Infantile sialic acid storage disorder; Sialuria, Finnish type (Salla disease)AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic

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

Refs: 4043964; 10546100; 10069709; 10581036; 10947946; 12121352; 12794687; 12794688; 15172005; 16170568; 19557856; 20101035; 20301643; 20637281Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC17A5 variants in ClinVar

12 Conditions Cataloged
Salla diseaseTotal: 570
Sialic acid storage disease, severe infantile typeTotal: 146
Inborn genetic diseasesTotal: 92
not providedTotal: 57
not specifiedTotal: 28
SLC17A5-related disorderTotal: 17
Focal segmental glomerulosclerosisTotal: 1
Lysosomal storage diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012434.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
5
clinvar
176
clinvar
 182
missense
2
clinvar
11
clinvar
176
clinvar
8
clinvar
1
clinvar
 198
nonsense
12
clinvar
28
clinvar
3
clinvar
 43
start loss
1
clinvar
4
clinvar
 5
frameshift
33
clinvar
53
clinvar
4
clinvar
 90
splice donor/acceptor (+/-2bp)
4
clinvar
25
clinvar
2
clinvar
 31
Total521221901841549

Highest pathogenic variant AF is 0.00036431136

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_012434.5RefSeqNP_036566.111MANE Select
ENST00000355773.6EnsemblENSP00000348019.511MANE Select
NM_001382629.1RefSeqNP_001369558.110Standard
NM_001382630.1RefSeqNP_001369559.110Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Sialuria or French Type Sialuria
  • Sialuria or French Type Sialuria
  • Amino Sugar Metabolism
  • G(M2)-Gangliosidosis: Variant B, Tay-sachs disease

Biological Process

  • ion transport
  • anion transport
  • amino acid transport
  • response to bacterium
  • sialic acid transport

Molecular Function

  • carbohydrate:proton symporter activity
  • sialic acid transmembrane transporter activity
  • sialic acid:proton symporter activity

Cellular Component

  • lysosome
  • lysosomal membrane
  • cytosol
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000355773
Coding exons
11
Length
60777
Individuals with no LoFs
125648
Homozygous LoFs
0
Heterozygous LoFs
100
Defined
125748
p
0.000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7142302630.8760.00001283179
Missense (PolyPhen)78101.010.772171167
Synonymous0.5658895.00.9260.000004781000
Loss of Function1.391825.60.7040.00000118309

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000550.00055rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000220.00022rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000550.00055rare
South Asian0.0000980.000098rare
Other0.000680.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transports glucuronic acid and free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation, this is required for normal CNS myelination. Mediates aspartate and glutamate membrane potential- dependent uptake into synaptic vesicles and synaptic-like microvesicles. Also functions as an electrogenic 2NO(3)(-)/H(+) cotransporter in the plasma membrane of salivary gland acinar cells, mediating the physiological nitrate efflux, 25% of the circulating nitrate ions is typically removed and secreted in saliva. {ECO:0000269|PubMed:10581036, ECO:0000269|PubMed:11751519, ECO:0000269|PubMed:15510212, ECO:0000269|PubMed:21781115, ECO:0000269|PubMed:22778404}.;
Disease
DISEASE: Infantile sialic acid storage disorder (ISSD) [MIM:269920]: Severe form of sialic acid storage disease. Affected newborns exhibit visceromegaly, coarse features and failure to thrive immediately after birth. These patients have a shortened life span, usually less than 2 years. {ECO:0000269|PubMed:10581036, ECO:0000269|PubMed:10947946}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.256

Intolerance Scores

LoFtool
0.882
RVIS EVS
0.06
RVIS percentile EVS
58.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.514

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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