SLC52A2

protein-coding

solute carrier family 52 member 2, the group of Solute carrier family 52

Gene summary

This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]

Previous symbols:

GPR172A

MANE transcript

NM_001363118.2

Inheritance

ClinVar variants

P:51U:274B:192

Top phenotype

Brown-Vialetto-Van Laere syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr8:144,333,957-144,361,286

External References & Databases

Ensembl (ENSG00000185803)

Transcript & Mutation Effects

hg38 • Region Span ~27.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brown-Vialetto-van Laere syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013867

Submitter: Labcorp Genetics (formerly Invitae)

Brown-Vialetto-van Laere syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013867

Submitter: ClinGen

The SLC52A2 gene has been associated with autosomal recessive Brown-Vialetto-Van Laere syndrome using the ClinGen Clinical Validity Framework as of 9/12/2017. This association was made using case-level data only. At least 12 missense and nonsense variants have been reported in humans. SLC52A2 was first associated with this disease in humans as early as 2012 (Johnson et al.). SLC52A2 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: 22864630, 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). 10 probands in 7 publications (22740598, 22864630, 23243084, 24616084, 24253200, 25807286, 29053833) are included in this curation. Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies and in vitro assays. In summary, SLC52A2 is definitively associated with autosomal recessive Brown-Vialetto-Van Laere syndrome. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 7/9/2018. 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 additional genetic evidence has been included and scoring adjusted to the current Gene Clinical Validity SOP Version 9. The new genetic evidence included 8 variants (5 missense, 1 frameshift, 1 nonsense, 1 small deletion) and 6 probands in 6 publications (PMID: 31064337, 30343981, 29961509, 29053833, 34737166, 27148561).

Brown-Vialetto-van Laere syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013867

Submitter: PanelApp Australia

Brown-Vialetto-van Laere syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013867

Submitter: G2P

Brown-Vialetto-van Laere syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013867

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Brown-Vialetto-Van Laere syndrome 2AR

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

Intervention: Audiologic/Otolaryngologic; Biochemical

Rationale: Individuals may manifest with progressive neurological dysfunction, and there is evidence that medical/dietary management (with high-dose riboflavin therapy) may be beneficial; Awareness of the potential for hearing loss may allow early interventions related to speech and language development

Refs: 22740598; 23107375; 23243084; 30343981

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC52A2 variants in ClinVar

10 Conditions Cataloged

Brown-Vialetto-van Laere syndrome 2Total: 466

Inborn genetic diseasesTotal: 155

not providedTotal: 125

SLC52A2-related disorderTotal: 52

not specifiedTotal: 46

Auditory neuropathy spectrum disorderTotal: 2

Brown-Vialetto-van Laere syndrome 1Total: 2

Mitochondrial diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001363118.2. 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			7 clinvar	174 clinvar	2 clinvar	183
missense	7 clinvar	17 clinvar	259 clinvar	15 clinvar	1 clinvar	299
nonsense	4 clinvar	2 clinvar	1 clinvar			7
start loss						0
frameshift	12 clinvar	6 clinvar	3 clinvar			21
splice donor/acceptor (+/-2bp)		3 clinvar	4 clinvar			7
Total	23	28	274	189	3	517

Highest pathogenic variant AF is 0.00017666632

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 96 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001363118.2	RefSeq	NP_001350047.1	4	MANE Select
ENST00000643944.2	Ensembl	ENSP00000496184.2	4	MANE Select
NM_001253815.2	RefSeq	NP_001240744.1	4	Standard
NM_001253816.2	RefSeq	NP_001240745.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism
Vitamin B2 (riboflavin) metabolism
Metabolism of water-soluble vitamins and cofactors
Metabolism of vitamins and cofactors

Biological Process

riboflavin metabolic process
riboflavin transport
viral entry into host cell

Molecular Function

virus receptor activity
protein binding
riboflavin transmembrane transporter activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000532887
Coding exons: 4
Length: 7138
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125734
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.845	300	262	1.15	0.0000164	2740
Missense (PolyPhen)		87	85.816	1.0138		1015
Synonymous	-3.13	176	131	1.35	0.00000907	1106
Loss of Function	1.63	6	12.1	0.494	5.28e-7	134

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000098	0.000097	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Riboflavin transporter. Riboflavin transport is Na(+)- independent but moderately pH-sensitive. Activity is strongly inhibited by riboflavin analogs, such as lumiflavin. Weakly inhibited by flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). In case of infection by retroviruses, acts as a cell receptor to retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A). {ECO:0000269|PubMed:12740431, ECO:0000269|PubMed:19307586, ECO:0000269|PubMed:20463145, ECO:0000269|PubMed:22864630, ECO:0000269|PubMed:23243084, ECO:0000269|PubMed:24253200, ECO:0000269|PubMed:27702554}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

RVIS EVS: -0.93
RVIS percentile EVS: 9.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
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