ClinVar

Description

The p.N215S pathogenic mutation (also known as c.644A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at nucleotide position 644. The asparagine at codon 215 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in patients with Fabry disease, hypertrophic cardiomyopathy (HCM), and renal disease (Davies JP et al. Hum Mol Genet. 1993;2(7):1051-3; Eng CM et al. Am J Hum Genet. 1993;53(6):1186-97; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Pasqualim G et al. Clin. Biochem., 2014 May;47:657-62; Militaru S et al. Curr Health Sci J Oct;45:272-277; Sheng B et al. Mol Genet Metab Rep, 2020 Sep;24:100596; Tian ML et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013 Apr;30:185-8; Duro G et al. Int J Mol Sci, 2018 Nov;19:; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Koulousios K et al. BMJ Open, 2017 Oct;7:e017098; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). This variant has also been observed to co-segregate with Fabry disease in multiple families (Tomberli B et al. Eur J Heart Fail. 2013;15(12):1363-73; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Spada M et al. Am J Hum Genet. 2006;79(1):31-40). It has been reported in the heterozygous state in a woman with Fabry disease and progressive cardiac dysfunction, who also had another heterozygous variant in GLA (p.C202R, c.604T>C) (McConnell EJ et al. Eur Heart J Case Rep, 2018 Dec;2:yty122). Individuals with this alteration have been reported to have later age of onset and fewer extracardiac findings when compared to individuals with classic Fabry disease (Thomas A et al. Molec Gen and Metab. 2015 Feb;114(2):S113; Frustaci A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:799-805; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Lavalle L et al. PLoS ONE, 2018 Apr;13:e0193550; Oder D et al. Circ Cardiovasc Genet, 2017 Oct;10:; Germain DP et al. Mol Genet Genomic Med, 2018 Apr;:). In several functional in vitro analyses, this alteration has demonstrated a reduction in alpha-galactosidase A enzyme activity, suggesting variable expressivity among clinical phenotypes depending on residual enzyme activity (Spada M et al. Am J Hum Genet. 2006;79(1):31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Ebrahim HY et al. J. Inherit. Metab. Dis., 2012 Mar;35:325-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.