MPZL2

protein-coding

myelin protein zero like 2, the group of V-set domain containing|Ig-like cell adhesion molecule family

Gene summary

Thymus development depends on a complex series of interactions between thymocytes and the stromal component of the organ. Epithelial V-like antigen (EVA) is expressed in thymus epithelium and strongly downregulated by thymocyte developmental progression. This gene is expressed in the thymus and in several epithelial structures early in embryogenesis. It is highly homologous to the myelin protein zero and, in thymus-derived epithelial cell lines, is poorly soluble in nonionic detergents, strongly suggesting an association to the cytoskeleton. Its capacity to mediate cell adhesion through a homophilic interaction and its selective regulation by T cell maturation might imply the participation of EVA in the earliest phases of thymus organogenesis. The protein bears a characteristic V-type domain and two potential N-glycosylation sites in the extracellular domain; a putative serine phosphorylation site for casein kinase 2 is also present in the cytoplasmic tail. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

EVA1

MANE transcript

NM_005797.4

Inheritance

ClinVar variants

P:25U:43B:16

Top phenotype

Deafness, autosomal recessive 111

gnomAD constraint

pLI —, LoF o/e 1.34

Max pathogenic AF

—

Genomic locus

chr11:118,253,416-118,264,536

External References & Databases

Ensembl (ENSG00000149573)

Transcript & Mutation Effects

hg38 • Region Span ~11.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

MPZL2 was first associated with autosomal recessive nonsyndromic hearing loss as early as 2018 (Wesdorp et al., PMID: 29961571; Bademci et al., PMID: 29982980). At least three unique variants (nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 15 probands in 4 publications (PMID: 29961571, 29982980, 32203226, 33234333). Variants in this gene segregated with disease in at least 11 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of disease is suspected to be homozygous or compound heterozygous loss of function. This gene-disease association is supported by a mouse model and expression studies (PMID: 29961571, 29982980). In summary, there is strong evidence to support the relationship between MPZL2 and autosomal recessive nonsyndromic hearing loss. Three years must elapse from the first proposal of the association to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This curation was approved by the Hearing Loss Gene Curation Expert Panel on 3/26/21 (SOP Version 8).

hearing loss, autosomal recessive 111STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029142

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessive 111DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0029142

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

hearing loss, autosomal recessive 111STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0029142

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 111AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 29961571; 29982980

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MPZL2 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 37

MPZL2-related disorderTotal: 33

not providedTotal: 21

Hearing loss, autosomal recessive 111Total: 19

not specifiedTotal: 8

Monogenic hearing lossTotal: 2

Hearing loss, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005797.4. 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				9 clinvar	1 clinvar	10
missense		1 clinvar	43 clinvar	5 clinvar	1 clinvar	50
nonsense		5 clinvar				5
start loss		2 clinvar				2
frameshift	2 clinvar	9 clinvar				11
splice donor/acceptor (+/-2bp)		6 clinvar				6
Total	2	23	43	14	2	84

Highest pathogenic variant AF is 0.0006754061

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005797.4	RefSeq	NP_005788.1	5	MANE Select
ENST00000278937.7	Ensembl	ENSP00000278937.2	5	MANE Select
NM_144765.3	RefSeq	NP_658911.1	5	Standard
ENST00000438295.2	Ensembl	ENSP00000408362.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Differentiation of white and brown adipocyte

Biological Process

homophilic cell adhesion via plasma membrane adhesion molecules
anatomical structure morphogenesis

Molecular Function

protein binding

Cellular Component

cytoskeleton
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278937
Coding exons: 5
Length: 11134
Individuals with no LoFs: 125280
Homozygous LoFs: 0
Heterozygous LoFs: 466
Defined: 125746
p: 0.00185

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.480	147	132	1.12	0.00000778	1397
Missense (PolyPhen)		55	42.578	1.2917		446
Synonymous	-0.290	49	46.5	1.05	0.00000253	431
Loss of Function	-1.08	16	12.0	1.34	6.94e-7	118

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.0026	0.0026	notable
Ashkenazi Jewish	0.0038	0.0038	notable
East Asian	0.0058	0.0058	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0017	0.0017	notable
South Asian	0.00085	0.00085	rare
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mediates homophilic cell-cell adhesion.;

Recessive Scores

pRec: 0.205

Intolerance Scores

LoFtool: 0.557
RVIS EVS: -0.05
RVIS percentile EVS: 50.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.132

Gene Damage Prediction

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