LRRC8A

protein-coding

leucine rich repeat containing 8 VRAC subunit A, the group of Volume regulated anion channel subunits

Gene summary

This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

LRRC8

MANE transcript

NM_019594.4

Inheritance

AD, AR

ClinVar variants

U:285B:233

Top phenotype

Agammaglobulinemia 5, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr9:128,882,133-128,918,039

External References & Databases

Ensembl (ENSG00000136802)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal agammaglobulinemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011096

Submitter: Orphanet

agammaglobulinemia 5, autosomal dominantLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013290

Submitter: Labcorp Genetics (formerly Invitae)

agammaglobulinemiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015977

Submitter: ClinGen

A single female patient with a heterozygous variant in LRRC8A was identified with agammaglobulinemia and B cell lymphopenia. T cells were not evaluated in this patient (PMID: 14660746, Sawada A., et al, 2003). However, in a spontaneous mouse model (ebo/ebo), which harbors a homozygous 2 bp frameshift variant in Lrrc8a, which truncates the 15 terminal leucine-rich repeats of the protein, LRCC8A, there is significantly decreased volume-regulated anion channel (VRAC) activity in T cells. These ebo/ebo mice have normal T cell development and function, and intact antibody responses to T-dependent antigens, in contrast to Lrcc8a -/- mice (PMID: 28192143, Platt C., et al, 2017). LRRC8A-formed VRAC appears to be important for T cell activation and function (PMID: 37925509, Wang Y, et al., 2023). Since other patients with B cell deficiency and heterozygous LRRC8A have not been identified, the curation is classified as Limited. p.Ile720ValfsTer?

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published (AR scope) No scorable published cases of biallelic (autosomal recessive) LRRC8A variants causing neurodevelopmental disorder were identified in the current literature review. Published genetic evidence total = 0/12 Genetic evidence – Our cases Family 1 – Two affected sisters. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5; segregation (additional affected sibling; conservative) = 0.5; case-control = 0; Family 1 total = 2.0 Total genetic evidence 2.0/12 Experimental evidence – Published Although LRRC8A has documented roles in neuronal physiology (volume-regulated anion channel function), no experimental evidence directly models or recapitulates an autosomal recessive neurodevelopmental disorder phenotype. Therefore, no experimental evidence is scored under the ClinGen framework for this GDR. Experimental evidence total = 0/6 Overall score Genetic evidence = 2.0 Experimental evidence = 0 Overall score = 2.0

Clinical Genomic Database (CGD)

Agammaglobulinemia 5, autosomal dominantAD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Congenital agammaglobulinemia has been described, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Comments: Only one individual (with a translocation affecting LRRC8A) has been described; This individual also demonstrated dysmorphic facies in addition to agammaglobulinemia

Refs: 14660746

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LRRC8A variants in ClinVar

5 Conditions Cataloged

not providedTotal: 486

not specifiedTotal: 112

LRRC8A-related disorderTotal: 30

Agammaglobulinemia 5, autosomal dominantTotal: 16

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019594.4. 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	212 clinvar	10 clinvar	224
missense			271 clinvar	11 clinvar		282
nonsense			4 clinvar			4
start loss						0
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	285	223	10	518

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 91 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019594.4	RefSeq	NP_062540.2	2	MANE Select
ENST00000372600.9	Ensembl	ENSP00000361682.4	2	MANE Select
NM_001127244.2	RefSeq	NP_001120716.1	2	Standard
NM_001127245.2	RefSeq	NP_001120717.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lrrc8aa	Danio rerio	Structure: trunk Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

lrrc8aa

Danio rerio

Structure: trunk

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Glucocorticoid Receptor Pathway
Nuclear Receptors Meta-Pathway
Transport of small molecules

Biological Process

pre-B cell differentiation
anion transport
cell volume homeostasis
response to osmotic stress
inorganic anion transport

Molecular Function

volume-sensitive anion channel activity
anion channel activity
protein binding
identical protein binding

Cellular Component

cytoplasm
plasma membrane
integral component of plasma membrane
cell surface
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259324
Coding exons: 2
Length: 35928
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.38	303	519	0.583	0.0000379	5295
Missense (PolyPhen)		125	271.11	0.46107		3002
Synonymous	-0.816	263	247	1.07	0.0000186	1667
Loss of Function	3.79	3	22.3	0.134	0.00000106	266

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity). {ECO:0000250|UniProtKB:Q80WG5, ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26530471, ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731, ECO:0000269|PubMed:29769723}.;
Disease: DISEASE: Agammaglobulinemia 5, autosomal dominant (AGM5) [MIM:613506]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:14660746}. Note=The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.0656
RVIS EVS: -1.57
RVIS percentile EVS: 3.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.780

Gene Damage Prediction

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