ClinVar Genomic variation as it relates to human health

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: 10080180, 12075506, 14627682, 19084400, 20980393). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 18796515, 25982065). 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: 14487). This variant is also known as c.1791C>T. This missense change has been observed in individuals with autosomal recessive Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and/or classical limb-girdle muscular dystrophy phenotype without heart involvement (PMID: 12768443, 18796515, 19432833, 23497705, 25286833, 27199538). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 527 of the LMNA protein (p.Arg527Cys).

This missense variant replaces arginine with cysteine at codon 527 of the LMNA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 dilated cardiomyopathy in the literature; it has been reported in an individual affected with atrial fibrillation (PMID: 35449878). This variant has been reported in both homozygous and compound heterozygous state in individuals affected with Hutchinson-Gilford progeria (PMID: 12768443, 19432833, 23497705) and in individuals affected with mandibuloacral dysplasia (PMID: 18796515, 25286833). It has also been reported in heterozygosity in an individual affected with Emery-Dreifuss muscular dystrophy type 2 (PMID: 27199538). This variant has been identified in 5/252174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in multiple individuals affected with autosomal recessive LMNA-associated disorders, its role in cardiomyopathy in heterozygous individuals is unknown. 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.

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-fold, lamin tail domain of the lamin A/C protein that is involved in binding to DNA and other proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in compound heterozygosity with p.Arg471Cys in an adult Caucasian woman affected with typical Hutchinson-Gilford progeria syndrome (PMID: 12768443). This variant has been reported in homozygosity in two Chinese children affected with atypical Hutchinson-Gilford progeria syndrome, and their heterozygous parents were asymptomatic (PMID: 19432833). This variant has also been reported in homozygosity in two Chinese siblings from a different family affected with Hutchinson-Gilford progeria syndrome accompanied by severe skeletal abnormalities (PMID: 23497705). This variant has been identified in 5/247418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While this variant has been observed in multiple individuals affected with autosomal recessive LMNA-associated disorders, its role in cardiomyopathy in heterozygous individuals is unknown. Available evidence is insufficient to determine the pathogenicity of this variant conclusively.