Submissions for variant NM_170707.4(LMNA):c.658C>T (p.Arg220Cys)

gnomAD frequency: 0.00002  dbSNP: rs370134870

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000247356	SCV000320673	uncertain significance	Cardiovascular phenotype	2021-11-12	criteria provided, single submitter	clinical testing	The p.R220C variant (also known as c.658C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 658. The arginine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with concerns for Emery-Dreifuss muscular dystrophy (Díaz-Manera J et al. Neuromuscul. Disord., 2016 Jan;26:33-40). 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.
Eurofins Ntd Llc (ga)	RCV000594818	SCV000704256	uncertain significance	not provided	2016-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000800454	SCV000940169	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 220 of the LMNA protein (p.Arg220Cys). This variant is present in population databases (rs370134870, gnomAD 0.004%). This missense change has been observed in individual(s) with LMNA-related conditions (PMID: 26573435, 31383942, 32880476). ClinVar contains an entry for this variant (Variation ID: 264626). 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.
Color Diagnostics, LLC DBA Color Health	RCV001179387	SCV001344041	uncertain significance	Cardiomyopathy	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 220 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 dilated cardiomyopathy (PMID: 32880476) and in individuals affected with cardiomyopathy and conduction defects (PMID: 31383942). It has also been reported in two unrelated individuals affected with Emery-Dreifuss muscular dystrophy (PMID: 26573435, DOI:10.1016/j.nmd.2007.06.126). The variant was in homozygous state in one of the two individuals, and the unaffected parents were both heterozygous carriers (DOI:10.1016/j.nmd.2007.06.126). This variant has also been reported in an individual from a cohort of participants undergoing whole exome sequencing in clinical research studies (PMID: 30122538). This variant has been identified in 6/251360 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	RCV000594818	SCV001777600	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Reported in a patient with Emery-Dreifuss muscular dystrophy in the published literature (Diaz-Manera et al., 2016). In an abstract by Olive et al. (2007), presumed to be reporting on the same patient, this individual is described as being homozygous for the p.(R220C) variant with a clinical presentation of muscle weakness, contractures, and cardiomyopathy, suggestive of autosomal recessive Emery-Dreifuss muscular dystrophy. Nonetheless, these details were not provided in the Diaz-Manera et al. (2016) peer-reviewed publication; Identified in individuals with cardiomyopathy and/or conduction defects, however, additional clinical and segregation information were not described (Park et al., 2020; Verdonschot et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663758, 32155092, 31383942, 32880476, 26573435, 10939567, 35011612, 30564623, 36264615)
CeGaT Center for Human Genetics Tuebingen	RCV000594818	SCV004124987	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing	LMNA: PM2:Supporting, PM5:Supporting, PP3