Submissions for variant NM_170707.4(LMNA):c.1058A>G (p.Gln353Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005198057	SCV005834026	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 353 of the LMNA protein (p.Gln353Arg). 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: 18646565, 29237675, 30078822, 37058558; internal data). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 34862408, 37058558). This variant disrupts the p.Gln353 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 20127487), which suggests that this may be a clinically significant amino acid residue. 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.
Ambry Genetics	RCV005358257	SCV006024333	pathogenic	Cardiovascular phenotype	2025-03-10	criteria provided, single submitter	clinical testing	The p.Q353R pathogenic mutation (also known as c.1058A>G), located in coding exon 6 of the LMNA gene, results from an A to G substitution at nucleotide position 1058. The glutamine at codon 353 is replaced by arginine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with laminopathies, including dilated cardiomyopathy, cardiac conduction disease, and dysrhythmia (Astejada MN et al. Acta Myol, 2007 Dec;26:159-64; Nishiuchi S et al. Circ Cardiovasc Genet, 2017 Dec;10; Nakajima K et al. Circ J, 2018 Oct;82:2707-2714; Yamada S et al. Sci Adv, 2023 Apr;9:eade7047). An animal model expressing this variant exhibited phenotype(s) consistent with dilated cardiomyopathy (Yamada S et al. Sci Adv, 2023 Apr;9:eade7047). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.