LMNA

Chr 1ADAR

lamin A/C

Also known as: CDCD1, CDDC, CMD1A, CMT2B1, EMD2, FPL, FPLD, FPLD2

NCBI Gene: 4000 ENSG00000160789 UniProt: P02545

The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1AMIM #115200

Charcot-Marie-Tooth disease, type 2B1MIM #605588

Emery-Dreifuss muscular dystrophy 2, autosomal dominantMIM #181350

Emery-Dreifuss muscular dystrophy 3, autosomal recessiveMIM #616516

Heart-hand syndrome, Slovenian typeMIM #610140

Hutchinson-Gilford progeriaMIM #176670

Lipodystrophy, familial partial, type 2MIM #151660

Malouf syndromeMIM #212112

Mandibuloacral dysplasiaMIM #248370

Muscular dystrophy, congenitalMIM #613205

Restrictive dermopathy 2MIM #619793

276

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— LMNA

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Gene-Disease Validity (ClinGen)

lipodystrophy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

64 Pathogenic / Likely Pathogenic· 118 VUS of 276 total submissions

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.21LOEUF

pLI 0.999

Z-score 4.75

OE 0.07 (0.03–0.21)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.37Z-score

OE missense 0.67 (0.60–0.74)

269 obs / 402.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.03–0.21)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.60–0.74)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95

0≤1.21.6

LoF obs/exp: 2 / 30.2Missense obs/exp: 269 / 402.7Syn Z: 0.55

ClinVar Variant Classifications

276 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic29

VUS118

Likely Benign91

Conflicting3

Pathogenic

Likely Pathogenic

118

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	6	5	0	35
Likely Pathogenic	9	18	2	0	29
VUS	3	106	9	0	118
Likely Benign	0	7	35	49	91
Benign	0	0	0	0	0
Conflicting	—				3
Total	36	137	51	49	276

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

View in ClinVar →

Protein Context — Lollipop Plot

LMNA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LMNA-related arrhythmogenic right ventricular cardiomyopathy

limited

ADUndeterminedUncertain

Cardiac

G2P ↗

LMNA-related dilated cardiomyopathy

definitive

ADUndeterminedAltered Gene Product Structure, Decreased Gene Product Level

Cardiac

G2P ↗

frameshift variantmissense variantstop gained NMD triggeringsplice donor variant NMD triggeringsplice acceptor variant NMD triggering

LMNA-related Hutchinson-Gilford progeria syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

LMNA-related lethal tight skin contracture syndrome

limited

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

LMNA-related Charcot-Marie-Tooth disease

limited

ARUndeterminedUncertain

Dev. DisordersSkin

G2P ↗

LMNA-related Emery-Dreifuss muscular dystrophy

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersSkin

G2P ↗

LMNA-related heart-hand syndrome, Slovenian type

moderate

ADUndeterminedUncertain

Skin

G2P ↗

LMNA-related familial partial lipodystrophy

definitive

ADUndeterminedAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

missense variantinframe deletioninframe insertion

LMNA-related restrictive dermopathy, lethal

definitive

ARLoss Of FunctionAbsent Gene Product

Skin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

LAMIN A/C; LMNA

MIM #150330 · *

Cardiomyopathy, dilated, 1A

MIM #115200