1-156137204-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5
The NM_170707.4(LMNA):c.1580G>T(p.Arg527Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,446,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1580G>T | p.Arg527Leu | missense_variant | 9/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.1580G>T | p.Arg527Leu | missense_variant | 9/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1580G>T | p.Arg527Leu | missense_variant | 9/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1580G>T | p.Arg527Leu | missense_variant | 9/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1446064Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 718404
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg527 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18796515, 19432833, 23497705, 25286833, 25982065). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 919926). This missense change has been observed in individuals with autosomal recessive mandibuloacral dysplasia type A and progeria (PMID: 22549407). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 527 of the LMNA protein (p.Arg527Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 19, 2020 | This missense variant replaces arginine with leucine at codon 527 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in homozygosity in three individuals (aged 4-10) from two Egyptian families affected with mandibuloacral dysplasia (PMID: 22549407). The probands’ mothers (aged 30 and 38) were heterozygous carriers and clinically unaffected. An ultrastructural study of the skin in the mothers has shown that some fibroblasts showed irregularities and invaginations of the nuclear membrane and were surrounded by the disrupted bundles of collagen fibers (PMID: 23775434). However, clinical relevance of this observation is not known. This variant has not been identified 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