MFSD8

protein-coding

major facilitator superfamily domain containing 8

Gene summary

This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]

Previous symbols:

CLN7

MANE transcript

NM_001371596.2

Inheritance

ClinVar variants

P:179U:340B:242

Top phenotype

Ceroid lipofuscinosis, neuronal, 7

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr4:127,917,799-127,966,034

External References & Databases

Ensembl (ENSG00000164073)

Transcript & Mutation Effects

hg38 • Region Span ~48.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronal ceroid lipofuscinosis 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: G2P

neuronal ceroid lipofuscinosis 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: Natera

macular dystrophy with central cone involvementSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014515

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

MFSD8 (also called CLN7) was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis in 2007 (Siintola et al. 2007, PMID 17564970). At least 20 unique variants have been reported in humans, including biallelic null variants (e.g., PMIDs 19177532, 30144815) as well as missense variants (PMIDs 18850119, 19277732, 25270050, 25333361, 30249282), from various ancestries. Evidence supporting this disease-gene association includes case-level genetic data and experimental data. More genetic evidence is available in the literature than was scored here because the maximum score for genetic evidence (12 pts.) has been reached. This gene has also been implicated in macular dystrophy; that asserted relationship was not assessed here. In summary, MFSD8 is definitively associated with autosomal recessive neuronal ceroid lipofuscinosis. This classification was approved by the ClinGen Epilepsy Gene Curation Working Group on 12/15/20 (SOP Version 8).

neuronal ceroid lipofuscinosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: PanelApp Australia

neuronal ceroid lipofuscinosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 7SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Ceroid lipofuscinosis, neuronal, 7AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Neurologic

Rationale: The condition can include severe sequelae, including seizures, and use of a patient-specific antisense oligonucleotide has been reported as benefiting clinical findings, including related to seizure control

Refs: 15074367; 15965709; 17564970; 19277732; 19201763; 18850119; 22612257; 31597037

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MFSD8 variants in ClinVar

21 Conditions Cataloged

Neuronal ceroid lipofuscinosis 7Total: 810

not providedTotal: 215

Late-infantile neuronal ceroid lipofuscinosisTotal: 166

Inborn genetic diseasesTotal: 101

not specifiedTotal: 83

Macular dystrophy with central cone involvementTotal: 50

MFSD8-related disordersTotal: 30

MFSD8-related disorderTotal: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371596.2. 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			10 clinvar	229 clinvar		239
missense	7 clinvar	27 clinvar	326 clinvar	13 clinvar		373
nonsense	20 clinvar	17 clinvar	2 clinvar			39
start loss		4 clinvar				4
frameshift	34 clinvar	21 clinvar				55
splice donor/acceptor (+/-2bp)	11 clinvar	38 clinvar	2 clinvar			51
Total	72	107	340	242	0	761

Highest pathogenic variant AF is 0.0000464718

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 97 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371596.2	RefSeq	NP_001358525.1	12	MANE Select
ENST00000641686.2	Ensembl	ENSP00000493218.2	12	MANE Select
NM_001363520.3	RefSeq	NP_001350449.1	10	Standard
NM_001363521.3	RefSeq	NP_001350450.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)

Biological Process

lysosome organization
regulation of autophagy
neuron development
transmembrane transport

Cellular Component

nucleoplasm
lysosomal membrane
integral component of membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296468
Coding exons: 12
Length: 48191
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125748
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.115	275	280	0.981	0.0000138	3351
Missense (PolyPhen)		83	104.1	0.79727		1189
Synonymous	-0.0179	97	96.8	1.00	0.00000485	1025
Loss of Function	1.27	22	29.5	0.747	0.00000154	331

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00013	0.00013	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be a carrier that transport small solutes by using chemiosmotic ion gradients. {ECO:0000305}.;
Disease: DISEASE: Macular dystrophy with central cone involvement (CCMD) [MIM:616170]: An ocular disease characterized by decreased visual acuity, slight pigmentary changes and color vision abnormalities, becoming apparent in the third to sixth decade of life. Fundus anomalies are variable and include bull's eye maculopathy, severe atrophy of central fovea, relatively spared fovea with surrounding atrophic ring, central retinal pigment epithelium and/or choroid changes, pale or atrophic peripapillary area, pale optic disk, relatively spared periphery, and slightly or moderately attenuated vessels. {ECO:0000269|PubMed:25227500}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.467
RVIS EVS: 0.24
RVIS percentile EVS: 69.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0863

Gene Damage Prediction

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