LRCH3

Chr 3

leucine rich repeats and calponin homology domain containing 3

NCBI Gene: 84859 ENSG00000186001 UniProt: Q96II8

Involved in septin cytoskeleton organization. Located in cytosol. [provided by Alliance of Genome Resources, Jul 2025]

Research

Involved in septin cytoskeleton organization. Located in cytosol. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— LRCH3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

101 VUS of 152 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.54

OE 0.58 (0.42–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.28Z-score

OE missense 0.96 (0.88–1.05)

371 obs / 386.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.42–0.81)

0≤0.351.4

Missense OE?0.96 (0.88–1.05)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 25 / 43.0Missense obs/exp: 371 / 386.4Syn Z: 0.30

This gene — mechanism propensity

0.76top 25%

GOF

0.75top 25%

LOF

0.3454th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

152 submitted variants in ClinVar

ClinVar

Classification Summary

VUS101

Likely Benign17

Benign4

101

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	101	0	0	101
Likely Benign	6	4	7	17
Benign	1	1	2	4
Total	108	5	9	122

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

44 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap LRCH3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →