Submissions for variant NM_170707.4(LMNA):c.694G>A (p.Gly232Arg)

dbSNP: rs267607609

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000519005	SCV000338003	uncertain significance	not provided	2016-02-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000519005	SCV000618277	pathogenic	not provided	2017-01-20	criteria provided, single submitter	clinical testing	The G232R variant in the LMNA gene has been reported previously in an individual with Emery-Dreifuss muscular dystrophy as a result of the c.694G>C nucleotide substitution (Rudenskaya et al.,2008). The Leiden Open Variant Database also includes one report of a de novo G232R (c.694G>A)substitution in an individual with atypical Emery-Dreifuss muscular dystrophy (Fokkema et al., 2011).Additionally, a different de novo missense substitution (G232E) has been reported at this position inan individual with Emery-Dreifuss muscular dystrophy (Boone et al. 2000). The G232R variant wasnot observed in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The G232R variant is a non-conservative amino acid substitution, that occurs within the alpha-helicalrod domain at a position where amino acids with similar properties to Glycine are tolerated acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function.We interpret G232R as a pathogenic variant
Invitae	RCV002521931	SCV002985876	pathogenic	Charcot-Marie-Tooth disease type 2	2022-11-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly232 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10939567, 16772334, 23077635, 25982065, 29676528, 29753763, 29893365). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 285122). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 18564364; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 232 of the LMNA protein (p.Gly232Arg).