Submissions for variant NM_170707.4(LMNA):c.848A>G (p.Asn283Ser)

gnomAD frequency: 0.00004  dbSNP: rs765241364

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621498	SCV000737998	uncertain significance	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	The p.N283S variant (also known as c.848A>G), located in coding exon 5 of the LMNA gene, results from an A to G substitution at nucleotide position 848. The asparagine at codon 283 is replaced by serine, an amino acid with highly similar properties. This variant was detected in a cohort of patients with with sporadic inclusion body myositis, and was possibly associated with Emery-Dreifuss muscular dystrophy; however, clinical details were not provided (Weihl CC et al. Neuromuscul Disord. 2015;25:289-96). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000701219	SCV000830010	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 283 of the LMNA protein (p.Asn283Ser). This variant is present in population databases (rs765241364, gnomAD 0.006%). This missense change has been observed in individual(s) with inclusion body myositis (PMID: 25617006). This variant is also known as N171S. ClinVar contains an entry for this variant (Variation ID: 519439). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Eurofins Ntd Llc (ga)	RCV000733487	SCV000861563	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172626	SCV001335689	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001187553	SCV001354373	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 283 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with inclusion body myositis (PMID: 25617006) and in an individual affected with familial partial lipodystrophy type 2 (doi:10.1210/jendso/bvab048.069). This variant has been identified in 8/282512 chromosomes 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.
GeneDx	RCV000733487	SCV001769716	uncertain significance	not provided	2023-10-06	criteria provided, single submitter	clinical testing	Reported, using alternative nomenclature (N171S), in a patient with inclusion body myositis; however, this individual also harbored a variant in the EMD gene (Weihl et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25617006, 10939567)
Fulgent Genetics, Fulgent Genetics	RCV002506508	SCV002812202	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	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000733487	SCV003814736	uncertain significance	not provided	2022-08-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002692	SCV004846228	uncertain significance	Primary dilated cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 283 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with inclusion body myositis (PMID: 25617006) and in an individual affected with familial partial lipodystrophy type 2 (doi:10.1210/jendso/bvab048.069). This variant has been identified in 8/282512 chromosomes 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.