ATP6V1E1

protein-coding

ATPase H+ transporting V1 subunit E1, the group of V-type ATPase subunits

Gene summary

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain E subunit isoforms. Pseudogenes for this gene have been found in the genome. [provided by RefSeq, Jul 2008]

Previous symbols:

ATP6E
ATP6V1E

MANE transcript

NM_001696.4

Inheritance

ClinVar variants

P:1U:54B:31

Top phenotype

Cutis laxa, autosomal recessive, type IIC

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr22:17,592,136-17,628,749

External References & Databases

Ensembl (ENSG00000131100)

Transcript & Mutation Effects

hg38 • Region Span ~36.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive cutis laxa type 2CLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0027462

Submitter: ClinGen

*ATP6V1E1* was first reported in relation to ATP6V1E1-CDG (also known as autosomal recessive cutis laxa 2C), an autosomal recessive congenital disorder of glycosylation, in 2016 (Alazami et al, PMID: 27023906). ATP6V1E1-CDG is characterized by the features of cutis laxa (wrinkly, inelastic, droopy skin), redundant skin, typical mask-like facial appearance, muscular hypotonia, cardiac abnormalities, and glycosylation and Golgi defects. Two variants, both missense, have been reported in 3 homozygous probands, each with an affected sibling with the same genotype (Alazami et al, 2016, PMID: 27023906; Van Damme et al, 2017, PMID: 28065471) (Genetic evidence, 1.2 points). This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product. ![](ATP6V1E1) encodes a subunit of the V1 domain of V-ATPase, a multi-subunit proton pump that maintains organelle luminal pH in eukaryotic cells. Variants in genes encoding other subunits of V-ATPase (*ATP6V0A2*, *ATP6V1A*) have been implicated in causing similar clinical features. Specifically, the clinical validity classification for *ATP6V0A2* with CDG has been classified as definitive by the ClinGen CDG GCEP. In addition, studies on skin biopsy samples and cultured fibroblasts from an affected individual show disruption of vesicular trafficking and abnormalities of elastic fibers and the extracellular matrix, consistent with the connective tissue features observed in patients (Van Damme et al, 2017, PMID: 28065471). Two zebrafish models with atp6v1e1b deficiency recapitulate features of the disorder, including dermis abnormalities, vascular defects, glycosylation defects, and Golgi abnormalities (Pottie et al, 2021, PMID: 34143769) (Experimental evidence: 4.5 points) In summary, there is limited evidence supporting the relationship between *ATP6V1E1* and ATP6V1E1-CDG (also known as autosomal recessive cutis laxa 2C). This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on May 1, 2024 (SOP version 10).

autosomal recessive cutis laxa type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0027462

Submitter: G2P

autosomal recessive cutis laxa type 2, classic typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009054

Submitter: Orphanet

autosomal recessive cutis laxa type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0027462

Submitter: PanelApp Australia

autosomal recessive cutis laxa type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0027462

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cutis laxa, autosomal recessive, type IICAR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can include early-onset cardiomyopathy, and awareness may allow early diagnosis and management

Refs: 28065471

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6V1E1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 139

not specifiedTotal: 27

Autosomal recessive cutis laxa type 2CTotal: 4

Cutis laxaTotal: 1

ATP6V1E1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001696.4. 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			2 clinvar	28 clinvar	1 clinvar	31
missense		1 clinvar	45 clinvar	2 clinvar		48
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	54	30	1	86

Highest pathogenic variant AF is 0.0000013682586

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001696.4	RefSeq	NP_001687.1	9	MANE Select
ENST00000253413.10	Ensembl	ENSP00000253413.5	9	MANE Select
NM_001039366.1	RefSeq	NP_001034455.1	8	Standard
NM_001039367.1	RefSeq	NP_001034456.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atp6v1e1b	Danio rerio	Structure: eye photoreceptor cell Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

atp6v1e1b

Danio rerio

Structure: eye photoreceptor cell

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mTOR signaling pathway - Homo sapiens (human)
Synaptic vesicle cycle - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

insulin receptor signaling pathway
ATP hydrolysis coupled proton transport
regulation of macroautophagy
transferrin transport
ion transmembrane transport

Molecular Function

protein binding
proton-exporting ATPase activity, phosphorylative mechanism
proton-transporting ATPase activity, rotational mechanism
ATPase binding

Cellular Component

lysosomal membrane
endosome
cytosol
microvillus
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253413
Coding exons: 9
Length: 36683
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125746
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.59	68	116	0.585	0.00000581	1500
Missense (PolyPhen)		5	19.43	0.25734		324
Synonymous	0.160	36	37.2	0.967	0.00000171	387
Loss of Function	2.88	3	15.1	0.199	7.26e-7	183

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Subunit of the peripheral V1 complex of vacuolar ATPase essential for assembly or catalytic function. V-ATPase is responsible for acidifying a variety of intracellular compartments in eukaryotic cells.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.0553
RVIS EVS: 0.04
RVIS percentile EVS: 56.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.895

Gene Damage Prediction

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