rs759829161
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_170707.4(LMNA):c.704G>A(p.Arg235His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R235C) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.704G>A | p.Arg235His | missense_variant | 4/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.704G>A | p.Arg235His | missense_variant | 4/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.704G>A | p.Arg235His | missense_variant | 4/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.704G>A | p.Arg235His | missense_variant | 4/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727232
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 29, 2023 | This missense variant replaces arginine with histidine at codon 235 of the LMNA 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 not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 3/282864 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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 235 of the LMNA protein (p.Arg235His). This variant is present in population databases (rs759829161, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 408986). 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 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2017 | A variant of uncertain significance has been identified in the LMNA gene. The R235H variant has not been published as pathogenic or been reported as benign to our knowledge. R235H is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R235H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | This missense variant replaces arginine with histidine at codon 235 of the lamin A/C protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/282864 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