LMNA |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- LMNA (HGNC:6636) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- lamin A/C
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- LMN1, CMD1A, LGMD1B, PRO1, LMNL1
- Alias symbols
- HGPS, MADA
- %HI
- 1.72(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 1(Read more about gnomAD pLI score)
- LOEUF
- 0.21(Read more about gnomAD LOEUF score)
- Cytoband
- 1q22
- Genomic Coordinates
-
GRCh37/hg19: chr1:156052364-156109872 NCBI Ensembl UCSC GRCh38/hg38: chr1:156082573-156140081 NCBI Ensembl UCSC - MANE Select Transcript
- NM_170707.4 ENST00000368300.9 (Read more about MANE Select)
- MANE Plus Clinical Transcript(s)
-
NM_005572.4 ENST00000677389.1 (Read more about MANE Plus Clinical) - Function
- Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:22431096, PubMed:23666920, PubMed:31548606). Lamin A and C are present in equal amounts in the lamina ... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-33283
Curation Status:
Complete
Issue Type:
Dosage Curation -
Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency
(3)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Last Evaluated:
12/14/2023
Haploinsufficiency (HI) Score Details
HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- dilated cardiomyopathy 1A Monarch
HI Evidence:
-
PUBMED:
31983221
Mazzarotta et al., (2020) evaluated rare variants in 56 putative dilated cardiomyopathy (DCM) genes in 1040 patients with DCM and 912 healthy controls, along with data review of 1498 patients with DCM testing from diagnostic laboratories via the Exome Aggregation Consortium Database. Truncating variants in LMNA were identified in 0.29% of the 1040 patients and 1.14% of the 1498 patients, compared to 0.01% of ExAC reference samples, and 0% of the healthy controls.
-
PUBMED:
31476771
Peretto et al., (2019) evaluated the neuromuscular and cardiovascular findings of 164 patients with LMNA variants from 124 families, including 97 probands and 67 relatives. Of the 164 patients, 7% had nonsense variants, 7% had frameshift, 9% had an insertion/deletion, 13% had a splice site, and 63% had a missense variant. The authors confirmed that compared with patients who had the cardiac phenotype, those with both neuromuscular and cardiac manifestations had fewer nonmissense mutations, which may suggest distinct pathogenic mechanism.
HI Evidence Comments:
The LMNA gene, encoding the highly conserved lamin A and C proteins, is a highly conserved gene that undergoes alternative splicing giving rise to prelamin A and lamin C, which can be found expressed in a wide range of tissues, including heart and skeletal muscles. Variants in LMNA are associated with a wide range of disorders including neuromuscular syndromes including Charcot-Marie-Tooth, Emery-Dreifuss muscular dystrophy, as well as Slovenian heart-hand syndrome, lipodystrophy, Malouf syndrome, mandibuloacral dysplasia, dilated cardiomyopathy, and Hutchinson-Gilford progeria. Some of reported syndromes have overlapping and variably present clinical phenotypes. LMNA-associated phenotypes include both autosomal dominant and recessive inheritance patterns. A large number (>400) of disease-associated LMNA variants have been reported; the vast majority are sequence-level alterations and are predominantly missense variants. However frameshift, nonsense, and intragenic deletions and duplications, which are capable of resulting in a loss-of-function, are also reported. Thus LMNA haploinsufficiency is a possible mechanism of pathogenicity, although it is not apparently the predominant mechanism. As yet, whole gene deletion of LMNA has not been reported in association with clinical phenotypes.
The presence of multiple independent publications with numerous loss-of-function-type variants, some of which include supportive functional data, provide evidence in support of LMNA haploinsufficiency. It should be noted there is extensive clinical heterogeneity, inheritance patterns, mutational spectrum, and lack of reports of focal whole gene deletions.
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
There is no evidence for triplosensitivity of LMNA at this time.
Genomic View
Select assembly:
(NC_000001.10)
(NC_000001.11)