rs769561386
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_170707.4(LMNA):c.1786G>A(p.Asp596Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D596D) has been classified as Likely benign.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1786G>A | p.Asp596Asn | missense_variant | 11/12 | ENST00000368300.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1786G>A | p.Asp596Asn | missense_variant | 11/12 | 1 | NM_170707.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000204 AC: 5AN: 245632Hom.: 0 AF XY: 0.0000299 AC XY: 4AN XY: 133786
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1460348Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 726468
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2021 | Reported in one individual with limb girdle muscular dystrophy who presented with DCM and heart failure (Correa and Gmez, 2007); Published functional studies using fibroblast cell lines derived from a patient harboring the D596N variant found that while chromosome 13 was maintained at the nuclear periphery, there was gross mislocalization of this chromosome, suggesting that D596N impacts the nuclear lamina's ability to interact with chromatin (Mewborn et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21818408, 21970986, 10939567, 24481844, 27507988, 27200088, 29907918, 21520333, 21179469, 18035816) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 12, 2018 | - - |
Muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 596 of the LMNA protein (p.Asp596Asn). This variant is present in population databases (rs769561386, gnomAD 0.005%). This missense change has been observed in individuals with Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816, 21520333). ClinVar contains an entry for this variant (Variation ID: 435774). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 16, 2023 | This missense variant replaces aspartic acid with asparagine at codon 596 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using fibroblasts derived from heterozygous carrier individuals for this variant have shown this variant causes abnormal localization of chromosome 13 within the nuclei, suggesting impaired interaction with chromatin (PMID: 21179469, 21818408). This variant has been reported in an individual affected with limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816) and in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 21520333). This variant has been identified in 6/277018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces aspartic acid with asparagine at codon 596 of the lamin A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 18035816) and in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 21520333). This variant has been identified in 6/277018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at