rs59270054
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_170707.4(LMNA):c.244G>A(p.Glu82Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E82Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.244G>A | p.Glu82Lys | missense_variant | 1/12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.244G>A | p.Glu82Lys | missense_variant | 1/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.244G>A | p.Glu82Lys | missense_variant | 1/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.244G>A | p.Glu82Lys | missense_variant | 1/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2015 | The E82K mutation was reported to segregate with DCM and atrial ventricular block in eight individuals from two Chinese families (Wang et al., 2006; Wu et al., 2010). E82K was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In vitro studies showed E82K significantly reduced expression and altered localization of connexin 43 (Sun et al., 2010). Studies in transgenic mice showed E82K activates the FAS and mitochondrial pathways of apoptosis in heart tissue (Lu et al., 2010). E82K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R72L, R72C, L85R, R89L) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 20497714, 21151901). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 66882). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and atrioventricular (AV) block (PMID: 16630578, 20155465). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 82 of the LMNA protein (p.Glu82Lys). - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 06, 2013 | The Glu82Lys variant in LMNA has been reported in at least 2 families with DCM a nd conduction system abnormalities, and segregated with disease in 8 affected re latives (Wang 2006, Wu 2010). It has not been identified in large population stu dies. Functional studies (in vitro) suggest an effect on protein function and mi ce carrying the variant exhibited clinical features of DCM (Wang 2006, Lu 2010, Sun 2010). In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) based upon segregation studies, absence fr om controls, and functional evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at