LRRC8A

Chr 9AD

leucine rich repeat containing 8 VRAC subunit A

Also known as: AGM5, HsLRRC8A, LRRC8, SWELL1

NCBI Gene: 56262 ENSG00000136802 UniProt: Q8IWT6 OMIM: 608360

This protein functions as an essential component of the volume-regulated anion channel (VRAC), which maintains cellular volume in response to osmotic changes and is required for B-cell and T-cell development. Mutations cause autosomal dominant agammaglobulinemia type 5, an immunodeficiency disorder resulting from defects in B-cell maturation. The gene is highly constrained against loss-of-function variants (pLI = 0.94, LOEUF = 0.35), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.351 OMIM phenotype

Clinical Summary— LRRC8A

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Gene-Disease Validity (ClinGen)

agammaglobulinemia · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.35LOEUF

pLI 0.944

Z-score 3.79

OE 0.13 (0.06–0.35)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.38Z-score

OE missense 0.58 (0.53–0.64)

303 obs / 519.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.13 (0.06–0.35)

0≤0.351.4

Missense OE0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE1.07

0≤1.21.6

LoF obs/exp: 3 / 22.3Missense obs/exp: 303 / 519.5Syn Z: -0.82

0.5575th %ile

GOF

0.72top 25%

LOF

0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.35

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNA heterozygous mutation in LRRC8A that truncates the 2 terminal LRRs was reported in a patient with agammaglobulinemia and absent B cells and was demonstrated to exert a dominant negative effect on T- and B-cell development in mice.PMID:28192143

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.