Submissions for variant NM_170707.4(LMNA):c.1280G>A (p.Arg427His)

gnomAD frequency: 0.00001  dbSNP: rs747139279

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767210	SCV000292898	uncertain significance	not provided	2015-05-21	criteria provided, single submitter	clinical testing	The R427H variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The R427H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (R419C, L421P, R435C) and in the same residue (R427G) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the R427H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved only in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Athena Diagnostics	RCV000767210	SCV000614025	uncertain significance	not provided	2022-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV001221759	SCV001393821	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 427 of the LMNA protein (p.Arg427His). This variant is present in population databases (rs747139279, gnomAD 0.0008%). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 245780). 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 with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002503919	SCV002817044	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-10-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998901	SCV004821078	uncertain significance	Primary dilated cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020920	SCV005030787	uncertain significance	Cardiovascular phenotype	2023-11-13	criteria provided, single submitter	clinical testing	The p.R427H variant (also known as c.1280G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1280. The arginine at codon 427 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in an individual tested for unspecified arrhythmia, and in an individual indicated as having unspecified cardiomyopathy and cardiac conduction disease on review of electronic medical record; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Park J et al. Genet Med, 2020 Jan;22:102-111). 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.