ClinVar Genomic variation as it relates to human health

Variant summary: LMNA c.212G>T (p.Ser71Ile) results in a non-conservative amino acid change located in the Intermediate filament, rod domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235094 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.212G>T has been reported in the literature in individuals affected with Cardiomyopathy or idiopathic Ventricular tachycardia. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

ClinVar contains an entry for this variant (Variation ID: 1786377). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 71 of the LMNA protein (p.Ser71Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 31383942). 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. 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.

The p.S71I variant (also known as c.212G>T), located in coding exon 1 of the LMNA gene, results from a G to T substitution at nucleotide position 212. The serine at codon 71 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was identified in an unselected cohort in an individual with cardiomyopathy and conduction defect based on electronic health record review; however, details were limited (Park J et al. Genet. Med., 2020 01;22:102-111). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10939567, 31383942)