MARVELD2

protein-coding

MARVEL domain containing 2, the group of MARVEL domain containing

Gene summary

The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

Previous symbols:

MRVLDC2
DFNB49

MANE transcript

NM_001038603.3

Inheritance

ClinVar variants

P:46U:128B:67

Top phenotype

Deafness, autosomal recessive 49

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr5:69,415,065-69,444,330

External References & Databases

Ensembl (ENSG00000152939)

Transcript & Mutation Effects

hg38 • Region Span ~29.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 49STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012420

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 49STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012420

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The MARVELD2 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/16/17. This association was made using case-level data. At least 7 variants (splice site, nonsense, frameshift) have been reported in humans. MARVELD2 was first associated with this disease in humans as early as 2006 (Riazuddin et al.). Association is seen in at least 7 probands in 4 publications (17186462, 18084694, 22903915, 27344577). Variants in this gene segregated with disease in at least 38 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Many variants were shown to evade nonsense mediated decay and produce viable mRNA transcripts. Mice with the p.R500X variant seen in humans had hearing loss and while the mRNA did not undergo NMD, no protein product was detected in the inner ear tricellular tight junctions, where the WT protein localizes. This gene-disease association is also supported by a knock-out mouse model and relevant expression and protein interaction studies. In summary, MARVELD2 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/18.

autosomal recessive nonsyndromic hearing loss 49STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012420

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 49MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012420

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 49AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 15538632; 17186462; 18084694

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MARVELD2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 167

Autosomal recessive nonsyndromic hearing loss 49Total: 70

Inborn genetic diseasesTotal: 55

not specifiedTotal: 44

MARVELD2-related disorderTotal: 27

MARVELD2-related disordersTotal: 5

Rare genetic deafnessTotal: 3

Hearing impairmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001038603.3. 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			3 clinvar	54 clinvar	1 clinvar	58
missense		1 clinvar	125 clinvar	12 clinvar		138
nonsense	8 clinvar	8 clinvar				16
start loss						0
frameshift	9 clinvar	14 clinvar				23
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar				6
Total	20	26	128	66	1	241

Highest pathogenic variant AF is 0.00027036414

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001038603.3	RefSeq	NP_001033692.2	6	MANE Select
ENST00000325631.10	Ensembl	ENSP00000323264.5	6	MANE Select
NM_001244734.2	RefSeq	NP_001231663.1	5	Standard
ENST00000413223.3	Ensembl	ENSP00000398922.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
EGFR1

Biological Process

sensory perception of sound
cell-cell junction organization
establishment of endothelial barrier
bicellular tight junction assembly

Molecular Function

protein binding

Cellular Component

cytoplasm
bicellular tight junction
integral component of membrane
basolateral plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000325631
Coding exons: 6
Length: 29219
Individuals with no LoFs: 125613
Homozygous LoFs: 0
Heterozygous LoFs: 135
Defined: 125748
p: 0.000537

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.197	308	318	0.969	0.0000183	3641
Missense (PolyPhen)		110	116.93	0.94077		1377
Synonymous	0.306	118	122	0.965	0.00000742	1092
Loss of Function	0.846	21	25.6	0.820	0.00000162	299

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00064	0.00064	rare
South Asian	0.00085	0.00085	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the formation of tricellular tight junctions and of epithelial barriers (By similarity). Required for normal hearing via its role in the separation of the endolymphatic and perilymphatic spaces of the organ of Corti in the inner ear, and for normal survival of hair cells in the organ of Corti (PubMed:17186462). {ECO:0000250|UniProtKB:Q3UZP0, ECO:0000269|PubMed:17186462}.;
Disease: DISEASE: Deafness, autosomal recessive, 49 (DFNB49) [MIM:610153]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:17186462}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.959
RVIS EVS: -0.35
RVIS percentile EVS: 29.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.249

Gene Damage Prediction

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