Submissions for variant NM_170707.4(LMNA):c.607G>A (p.Glu203Lys)

dbSNP: rs61195471

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211790	SCV000065048	likely pathogenic	Primary dilated cardiomyopathy	2018-02-20	criteria provided, single submitter	clinical testing	The p.Glu203Lys variant in LMNA has been reported in 2 individuals with dilated cardiomyopathy, and in one family segregated with DCM in two individuals and con duction system disease in another 6 individuals (Jakobs 2001, LMM data). It was also absent from large population studies. This variant has been reported in Cli nVar (Variation ID: 48070). In vitro functional studies provide some evidence th at the p.Glu203Lys variant may impact protein function (Cowan 2010), while anoth er had inconclusive findings (Zwerger 2013). However, these types of assays may not accurately represent biological function. Finally, another missense variant at this position has been reported to segregate with DCM (p.Glu203Gly; Fatkin 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu203Lys variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_ Strong, PM2, PS3_Supporting, PS4_Supporting.
GeneDx	RCV000057427	SCV000293035	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	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; Functional studies suggest that the E203K variant disrupts lamin A localization, resulting in protein aggregation and increased cell death (Zhang et al., 2008; Cowen et al., 2010); Reported in ClinVar (ClinVar Variant ID# 48070; ClinVar); This variant is associated with the following publications: (PMID: 29764566, 10580070, 23427149, 18606848, 23582089, 18585512, 18795223, 22464770, 27374873, 11561226, 30934932, 31514951, 31983221, 32455078, 32719615, 32471220, 20160190, 26199943, 20301717, 24556839, 23475188, 22886719, 21639948, 20079693, 19282183, 10939567)
Ambry Genetics	RCV000618699	SCV000737218	pathogenic	Cardiovascular phenotype	2023-10-16	criteria provided, single submitter	clinical testing	The p.E203K pathogenic mutation (also known as c.607G>A), located in coding exon 3 of the LMNA gene, results from a G to A substitution at nucleotide position 607. The glutamic acid at codon 203 is replaced by lysine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals with dilated cardiomyopathy (DCM) and/or conduction system disease and has been shown to segregate with disease phenotype in one large family (Jakobs PM et al. J. Card. Fail. 2001;7:249-56; Lakdawala NK et al. J. Card. Fail. 2012;18:296-303). In addition, functional studies have demonstrated deficient LMNA protein function both in cell lines expressing E203K and in fibroblasts from patients heterozygous for this mutation (Zhang YQ et al. J. Cell Biol. 2008;182:35-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3:6-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000653912	SCV000775802	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 203 of the LMNA protein (p.Glu203Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 11561226, 22464770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48070). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 18606848, 20160190). This variant disrupts the p.Glu203 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 10580070, 18795223), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000057427	SCV001715326	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5, PP1_strong, PP3
GeneReviews	RCV000055999	SCV000087055	not provided	Dilated cardiomyopathy 1A		no assertion provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057427	SCV000088541	not provided	not provided		no assertion provided	not provided
GenomeConnect, ClinGen	RCV001824588	SCV002074884	not provided	Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; 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		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-09-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.