Submissions for variant NM_170707.4(LMNA):c.1745G>T (p.Arg582Leu)

dbSNP: rs57830985

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624034	SCV000742811	uncertain significance	Inborn genetic diseases	2017-09-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001524890	SCV001734861	uncertain significance	Cardiomyopathy	2020-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 582 of the lamin A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with diabetes mellitus, hypertriglyceridemia, and non-alcoholic fatty liver disease (PMID: 32012908). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002404709	SCV002712182	uncertain significance	Cardiovascular phenotype	2021-08-18	criteria provided, single submitter	clinical testing	The p.R582L variant (also known as c.1745G>T), located in coding exon 11 of the LMNA gene, results from a G to T substitution at nucleotide position 1745. The arginine at codon 582 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual reported to have some features consistent with familial partial lipodystrophy (FPLD) (Desgrouas C et al. Cells, 2020 01;9:[Epub ahead of print]). Another alteration at the same codon, p.R582H (c.1745G>A), has been reported in multiple unrelated individuals with atypical FPLD and has also been reported to segregate with disease (Speckman RA et al. Am J Hum Genet, 2000 Apr;66:1192-8; Garg A et al. J Clin Endocrinol Metab, 2001 Jan;86:59-65; Boschmann M et al. J Clin Endocrinol Metab, 2010 Apr;95:1634-43; Akinci B et al. Metabolism, 2017 07;72:109-119; Patni N et al. J Clin Endocrinol Metab, 2019 04;104:1099-1108; Soyaltin UE et al. Clin Diabetes Endocrinol, 2020 Jul;6:13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506519	SCV002815512	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	2021-12-07	criteria provided, single submitter	clinical testing
Invitae	RCV002533137	SCV002965728	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-08-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg582 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10739751, 11231979, 20130076, 28641778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 521983). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 582 of the LMNA protein (p.Arg582Leu). 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: 32012908).