ClinVar Genomic variation as it relates to human health

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual with a personal and family history of slowly progressive proximal muscle weakness in addition to early onset atrial fibrillation and conduction disease (Chen et al., 2013); This variant is associated with the following publications: (PMID: 24503780, 36984439, 23360689)

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 245721). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or limb-girdle muscular dystrophy (PMID: 23360689, 24503780). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329).

The c.513+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the LMNA gene. This variant has been detected in an individual reported to have features consistent with skeletal myopathy, cardiac dysrhythmias, and dilated cardiomyopathy (Chen CH et al. BMC Res Notes, 2013 Jan;6:32). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.