ClinVar Genomic variation as it relates to human health

PS3, PS4, PM2, PP3

This sequence change results in a frameshift in the LMNA gene (p.Thr655Asnfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the LMNA protein and extend the protein by 38 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with familial partial lipodystrophy (FPLD2) and dilated cardiomyopathy (PMID: 17711925, 25163546, 25819867). This variant is also known as c.1870_1871insG (p.R624fs). ClinVar contains an entry for this variant (Variation ID: 66878). For these reasons, this variant has been classified as Pathogenic.

The c.1961dupG pathogenic mutation, located in coding exon 11 of the LMNA gene, results from a duplication of G at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.T655Nfs*49). This mutation has been identified in multiple homozygous individuals with familial partial lipodystrophy type 2 (FPLD2) (Decaudain A et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4835-44; Le Dour C et al. J. Clin. Endocrinol. Metab., 2011 May;96:E856-62; Andre P et al. Am. Heart J., 2015 Apr;169:587-93). In one study, 7/10 homozygous and 3/25 heterozygous individuals demonstrated cardiolaminopathy manifestations (Andre P et al. Am. Heart J., 2015 Apr;169:587-93). This mutation was also identified in a cohort of individuals with dilated cardiomyopathy (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of LMNA, is not expected to trigger nonsense-mediated mRNA decay, impacts the last 10 amino acids, and results in the elongation of the protein by 38 amino acids. The exact functional impact of the added amino acids is unknown at this time; however, the resulting protein from patient fibroblasts showed no evidence of posttranslational farnesylation CSIM site (Le Dour C et al. J. Clin. Endocrinol. Metab., 2011 May;96:E856-62). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Reported in association with dilated cardiomyopathy, though clinical details were not provided (Haas et al., 2015); Reported as a founder mutation in Creole individuals from Reunion Island, and described to have a dose-dependent effect with more severe clinical manifestations in homozygous individuals compared to heterozygous individuals; non-penetrance in heterozygous individuals has been observed (Le Dour et al., 2011; Andre et al., 2015); Cultured fibroblasts from individuals heterozygous and homozygous this this variant showed misshapen nuclei, and fibroblasts homozygous for the variant demonstrated increased oxidative stress and features of premature senescence (Le Dour et al., 2011); Frameshift variant predicted to result in replacement of the last 10 amino acids with 48 different amino acids; Not observed in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 66878; ClinVar); This variant is associated with the following publications: (PMID: 25819867, 25163546, 21346069, 17711925, 10939567, 35528128, 34292171)

This variant inserts 1 nucleotide in exon 11 of the lamin A transcript (NM_170707.3), causing a frameshift in the last exon and addition of 49 new amino acids before introducing a stop codon. This variant represents a single nucleotide insertion in the 3' untranslated region of the lamin C transcript (NM_005572.3: c.*986dup). This results in a protein product that is 39 amino acids longer than the normal protein product. A functional study has shown that this variant causes abnormal post-translational maturation and premature senescence (PMID: 21346069). This variant has been reported as a founder variant from Reunion Island in association with lipodystrophy and laminopathy, showing a more severe phenotype in homozygous individuals than in heterozygous individuals (PMID: 17711925, 21346069, 25819867, 34292171). This variant has been reported in the heterozygous state in an individual affected with dilated cardiomyopathy (PMID: 25163546) and in the homozygous state in several individuals affected with dilated cardiomyopathy (PMID: 34292171). It has also been reported in an individual affected with sudden cardiac arrest (PMID: 35528128); the variant was also identified in 3 unaffected family members. 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.

Variant confirmed as disease-causing by referring clinical team