SLC52A3

protein-coding

solute carrier family 52 member 3, the group of Solute carrier family 52

Gene summary

This gene encodes a riboflavin transporter protein that is strongly expressed in the intestine and likely plays a role in intestinal absorption of riboflavin. The protein is predicted to have eleven transmembrane domains and a cell surface localization signal in the C-terminus. Mutations at this locus have been associated with Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. [provided by RefSeq, Mar 2012]

Previous symbols:

C20orf54

MANE transcript

NM_033409.4

Inheritance

ClinVar variants

P:44U:224B:160

Top phenotype

Brown-Vialetto-Van Laere syndrome 1; Fazio-Londe disease

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr20:760,080-776,015

External References & Databases

Ensembl (ENSG00000101276)

Transcript & Mutation Effects

hg38 • Region Span ~15.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brown-Vialetto-van Laere syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: Genomics England PanelApp

Brown-Vialetto-van Laere syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: PanelApp Australia

Brown-Vialetto-van Laere syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: Labcorp Genetics (formerly Invitae)

Brown-Vialetto-van Laere syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: Ambry Genetics

progressive bulbar palsyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008890

Submitter: LiferaOmics

Genetic evidence – Published PMID: 21110228 – Family 1 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (affected sibling) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 21110228 – Family 2 – one proband. Case-level (AR compound heterozygous; one predicted null and one non-LOF; variants evaluated individually then combined) = 1.6; Segregation = 0; Case-control = 0 Family 2 total = 1.6 PMID: 28580161 – Family 3 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 3 total = 1.0 Published genetic evidence total = 4.1 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Total genetic evidence (published AR + our cases) 4.1 (published AR) + 1.0 (our case) = 5.1 / 12 ________________________________________ Experimental evidence – Published (conservative scoring) PMID: 21110228 – Demonstrates biochemical flavin deficiency in affected patients and clinical/biochemical improvement following high-dose riboflavin supplementation, supporting a riboflavin transport defect mechanism. Functional alteration (patient-based biochemical evidence; conservative) = 0.5 PMID: 27272163 – Slc52a3 disruption in vivo results in severe riboflavin deficiency and lethality, with rescue by riboflavin supplementation, supporting the essential role of SLC52A3-mediated riboflavin transport. Model system evidence (animal model; conservative) = 1.0 Gene function / biological plausibility (riboflavin transporter essential for flavin-dependent mitochondrial metabolism) = 0.5 Experimental evidence total = 2.0 / 6 ________________________________________ Overall score Genetic evidence = 5.1 Experimental evidence = 2.0 Overall score = 7.1 / 18

Brown-Vialetto-van Laere syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: ClinGen

The relationship between SLC52A3 and autosomal recessive Brown-Vialetto-Van Laere syndrome (BVVL) was evaluated using the ClinGen Clinical Validity Framework as of 9/12/2018. Variants in SLC52A3 were first reported in humans with this disease as early as 2010 (Green et al., PMID 20206331). SLC52A3 is associated with the childhood onset neurodegenerative syndrome Brown–Vialetto–Van Laere (BVVL) which is characterized by sensorineural hearing loss and ponto-bulbar palsy (PMID: 26976849, 30420458). Whilst these are the most common clinical features, BVVL can also present without either symptom (PMID: 26973221). The standard treatment for BVVL is riboflavin supplementation which is associated with favourable clinical outcomes (PMID: 26973221). At least 25 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and mouse models, a drosophila model, biochemical function studies implicating the gene's role in riboflavin uptake, and functional alteration studies showing that alteration to the gene impairs riboflavin uptake which appears to be the mechanism for disease. Variants in this gene have been reported in at least 22 probands in 5 publications (PMIDs: 29053833, 25462087, 21110228, 20206331, 22824638). Variants in this gene segregated with disease in 2 additional family members. In summary, SLC52A3 is definitively associated with autosomal recessive Brown-Vialetto-Van Laere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 9/18/2018. It was reevaluated on 6/21/2023 in collaboration with the Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP. As a result of this reevaluation, the classification did not change. However, scoring was adjusted to the current Gene Clinical Validity SOP Version 9. It is also worth highlighting that in the mouse and drosophila models (PMID: 27272163, 29053833) riboflavin supplementation was able to restore normal function and replicates the rescue of the phenotypes observed in humans with Brown-Vialetto-Van Laere syndrome (PMID: 30420458).

progressive bulbar palsyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008890

Submitter: Ambry Genetics

Brown-Vialetto-van Laere syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024537

Submitter: G2P

Clinical Genomic Database (CGD)

Brown-Vialetto-Van Laere syndrome 1; Fazio-Londe diseaseAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Individuals typically manifest with progressive neurological dysfunction, including hearing loss, and there is evidence that high-dose riboflavin therapy may be beneficial in some individuals

Refs: 13900073; 5969547; 5563586; 7425580; 7229669; 2325091; 16122634; 20206331; 20920669; 21110228; 22098162; 22740598; 22633641; 22211384; 23107375

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC52A3 variants in ClinVar

10 Conditions Cataloged

Brown-Vialetto-van Laere syndrome 1Total: 401

Inborn genetic diseasesTotal: 121

not providedTotal: 92

SLC52A3-related disorderTotal: 49

not specifiedTotal: 38

Progressive bulbar palsy of childhoodTotal: 14

Auditory neuropathyTotal: 2

Madras motor neuron diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033409.4. 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				147 clinvar	2 clinvar	149
missense	3 clinvar	16 clinvar	219 clinvar	11 clinvar		249
nonsense	10 clinvar	3 clinvar	2 clinvar			15
start loss			1 clinvar			1
frameshift	5 clinvar	6 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	19	25	224	158	2	428

Highest pathogenic variant AF is 0.00012581049

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033409.4	RefSeq	NP_212134.3	4	MANE Select
ENST00000645534.1	Ensembl	ENSP00000494193.1	4	MANE Select
NM_001370085.1	RefSeq	NP_001357014.1	4	Standard
NM_001370086.1	RefSeq	NP_001357015.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vitamin digestion and absorption - Homo sapiens (human)
Metabolism
Vitamin B2 (riboflavin) metabolism
Metabolism of water-soluble vitamins and cofactors
Metabolism of vitamins and cofactors

Biological Process

riboflavin metabolic process
sensory perception of sound
riboflavin transport
cellular response to heat

Molecular Function

riboflavin transmembrane transporter activity

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
apical plasma membrane
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217254
Coding exons: 4
Length: 8408
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125746
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	214	272	0.787	0.0000165	2969
Missense (PolyPhen)		44	73.358	0.5998		863
Synonymous	-0.517	130	123	1.06	0.00000798	1025
Loss of Function	2.08	5	13.1	0.380	5.73e-7	141

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transporter for riboflavin, which must be obtained as a nutrient via intestinal absorption. Riboflavin transport is Na(+)- independent at low pH but significantly reduced by Na(+) depletion under neutral pH conditions. Activity is strongly inhibited by riboflavin analogs, such as lumiflavin, flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), by methylene blue, and to a lesser extent by amiloride. {ECO:0000269|PubMed:20463145, ECO:0000269|PubMed:22273710, ECO:0000269|PubMed:24264046, ECO:0000269|PubMed:27702554}.;
Disease: DISEASE: Fazio-Londe disease (FALOND) [MIM:211500]: A rare neurological disease characterized by progressive weakness of the muscles innervated by cranial nerves of the lower brain stem. It may present in childhood with severe neurological deterioration with hypotonia, respiratory insufficiency leading to premature death, or later in life with bulbar weakness which progresses to involve motor neurons throughout the neuroaxis. Clinical manifestations include dysarthria, dysphagia, facial weakness, tongue weakness, and fasciculations of the tongue and facial muscles. {ECO:0000269|PubMed:21110228}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

RVIS EVS: 0.09
RVIS percentile EVS: 60.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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