rs58978449
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_170707.4(LMNA):c.781_783delAAG(p.Lys261del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
LMNA
NM_170707.4 conservative_inframe_deletion
NM_170707.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.22
Genes affected
LMNA (HGNC:6636): (lamin A/C) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_170707.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 1-156134942-TAAG-T is Pathogenic according to our data. Variant chr1-156134942-TAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134942-TAAG-T is described in Lovd as [Pathogenic]. Variant chr1-156134942-TAAG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156134942-TAAG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.781_783delAAG | p.Lys261del | conservative_inframe_deletion | 4/12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.781_783delAAG | p.Lys261del | conservative_inframe_deletion | 4/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.781_783delAAG | p.Lys261del | conservative_inframe_deletion | 4/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.781_783delAAG | p.Lys261del | conservative_inframe_deletion | 4/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 27, 2017 | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2018 | The c.781_783delAAG pathogenic variant has been reported in multiple individuals with autosomal dominant Emery Dreifuss muscular dytrophy, including as a de novo change (Bonne et al., 2000, Rudenskaya et al., 2008, Rankin et al., 2006). The c.781_783delAAG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.781_783delAAG variant results in an in-frame deletion of a single Lysine residue, denoted p.Lys261del. This varaint occurs at a position that is conserved across species. Therefore, based on the currently available information, we interpret c.781_783delAAG as a pathogenic variant, and its presence is consistent with an LMNA-related disorder in this individual. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 11, 2023 | ClinVar contains an entry for this variant (Variation ID: 48080). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects LMNA function (PMID: 22068161). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 10908904, 10939567, 11503164, 22068161). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.781_783del, results in the deletion of 1 amino acid(s) of the LMNA protein (p.Lys261del), but otherwise preserves the integrity of the reading frame. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 18, 2011 | The Lys261del variant has been reported in 2 individuals with a clinical diagnos is and family history of Emery-Dreifuss muscular dystrophy. The variant was abse nt from over 680 control chromosomes, supporting a pathogenic role (Bonne 2000, Brown 2001, Felice 2000). In addition, our laboratory has detected this variant in one individual whose clinical features were consistent with those of the prev iously published patients, further increasing the likelihood that this variant i s pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2023 | The c.781_783delAAG variant (also known as p.K261del) is located in coding exon 4 of the LMNA gene. This variant results from an in-frame AAG deletion at nucleotide positions 781 to 783. This results in the in-frame deletion of a lysine at codon 261. This alteration has been reported in subjects with LMNA-associated disease and has been reported as de novo (Felice KJ et al. Neurology, 2000 Jul;55:275-80; Bonne G et al. Ann Neurol, 2000 Aug;48:170-80; Brown CA et al. Am J Med Genet, 2001 Sep;102:359-67; Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at