1-156138539-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_170707.4(LMNA):c.1750C>T(p.Arg584Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,612,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R584H) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1750C>T | p.Arg584Cys | missense_variant | Exon 11 of 12 | ENST00000368300.9 | NP_733821.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000823 AC: 2AN: 243034Hom.: 0 AF XY: 0.00000753 AC XY: 1AN XY: 132742
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460258Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 726436
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74502
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
This missense variant replaces arginine with cysteine at codon 584 of the lamin A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30429050). This variant has been identified in 2/243034 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. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 584 of the LMNA protein (p.Arg584Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 476826). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg584 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10999845, 11078466, 22700598, 31194872, 33502018, 36397776). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
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Primary dilated cardiomyopathy Uncertain:1
This missense variant replaces arginine with cysteine at codon 584 of the lamin A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30429050). This variant has been identified in 2/243034 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. -
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2;C5979868:Dilated cardiomyopathy 1A Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R584C variant (also known as c.1750C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1750. The arginine at codon 584 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual from a dilated cardiomyopathy cohort; however, details were limited (Halliday BP et al. Lancet. 2019 Jan;393(10166):61-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at