LAMA5

Chr 20

laminin subunit alpha 5

Also known as: BBDS2, NPHS26

NCBI Gene: 3911 ENSG00000130702 UniProt: O15230

The protein is the alpha-5 subunit of laminin that mediates cell attachment, migration and tissue organization during embryonic development and regulates skeletal development through integrin-mediated signaling. Mutations cause bent bone dysplasia syndrome and nephrotic syndrome with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variation (LOEUF 0.31), affecting primarily skeletal and renal systems.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the vertebrate laminin alpha chains. Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. The protein encoded by this gene is the alpha-5 subunit of of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523). [provided by RefSeq, Jun 2013]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.31

Clinical Summary— LAMA5

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Gene-Disease Validity (ClinGen)

LAMA5-related multisystemic syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 1045 VUS of 2364 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LAMA5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.006

Z-score 9.48

OE 0.24 (0.19–0.31)

Highly constrained

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

Missense Constraint?

-0.27Z-score

OE missense 1.02 (0.98–1.05)

2301 obs / 2264.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.24 (0.19–0.31)

0≤0.351.4

Missense OE?1.02 (0.98–1.05)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 44 / 182.1Missense obs/exp: 2301 / 2264.6Syn Z: -6.45

This gene — mechanism propensity

0.6840th %ile

GOF

0.6637th %ile

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative 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.

LOF70% of P/LP variants are LoF · LOEUF 0.31

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

2364 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic20

VUS1045

Likely Benign854

Benign289

Conflicting69

Pathogenic

Likely Pathogenic

1045

VUS

854

Likely Benign

289

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	0	0	0	7
Likely Pathogenic	12	8	0	0	20
VUS	17	989	29	10	1,045
Likely Benign	0	110	248	496	854
Benign	1	69	141	78	289
Conflicting	—				69
Total	37	1,176	418	584	2,284

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap LAMA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →