ClinVar

Description

The p.S573L variant (also known as c.1718C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1718. The serine at codon 573 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with diseases on the laminopathy spectrum, including individuals with dilated cardiomyopathy (DCM), at least one of whom also had variants in other cardiac-related genes (Taylor MR et al. J. Am. Coll. Cardiol., 2003 Mar;41:771-80; Pasotti M et al. J. Am. Coll. Cardiol., 2008 Oct;52:1250-60; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Dal Ferro M et al. Heart, 2017 11;103:1704-1710), as well as individuals with unspecified primary electrical disease (Proost D et al. J Mol Diagn, 2017 05;19:445-459), familial partial leukodystrophy type 2 (Lanktree M et al. Clin. Genet., 2007 Feb;71:183-6), limb-girdle dystrophy (Benedetti S et al. Neurology, 2007 Sep;69:1285-92; Bernasconi P et al. Nucleus, 2018 01;9:292-304), and Emery-Dreifuss muscular dystrophy (Bernasconi P et al. Nucleus, 2018 01;9:292-304). This variant was also detected as heterozygous in an individual with hypertrophic cardiomyopathy (HCM) and metabolic syndrome (Francisco ARG et al. Rev Port Cardiol, 2017 Sep;36:669.e1-669.e4). In addition, this variant was described as homozygous in an individual with a novel arthropathy phenotype demonstrating progeroid features, generalized lipodystrophy, and sclerodermatous skin (Van Esch H et al. J. Clin. Endocrinol. Metab., 2006 Feb;91:517-21); this patient's heterozygous son and presumed obligate carrier mother were unaffected with no reported cardiac findings. This variant has also been detected in cohorts not selected for the presence of LMNA-related disease; however, details were limited (Kasak L et al. Hum Reprod. 2022 Jun;37(7):1652-1663; Quaio CRDC et al. Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964). In one experimental study, this alteration was found to restore responsiveness in LMNA-deficient fibroblasts (Nitta RT et al. Mol Cell Biol, 2006 Jul;26:5360-72). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.