ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.607G>A (p.Glu203Lys) (rs61195471)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-08-24 criteria provided, single submitter clinical testing The E203K pathogenic variant in the LMNA gene has previously been reported in association with DCM (Jakobs et al., 2001; Lakdawala et al., 2012). Jakobs et al. (2001) reported that E203K segregated with disease in multiple affected relatives with DCM and/or conduction system disease from one family. Additionally, E203K has been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The E203K variant results in a non-conservative amino acid substitution occurring within the coil 1B and rod region. 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). Finally, other missense variants in the same residue (E203G, E203V) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), further supporting the functional importance of this residue.In summary, E203K in the LMNA gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000618699 SCV000737218 pathogenic Cardiovascular phenotype 2017-11-16 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000653912 SCV000775802 pathogenic Charcot-Marie-Tooth disease, type 2 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 203 of the LMNA protein (p.Glu203Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy (DCM) and progressive conduction disease in a single family and has been reported in an individual with DCM (PMID: 11561226, 22464770). ClinVar contains an entry for this variant (Variation ID: 48070). Experimental studies have shown that this missense change alters protein function and subcellular localization in vitro (PMID: 18606848, 20160190). Missense variants in the same residue (p.Glu203Gly, p.Glu203Val) have been reported in individuals affected with LMNA-related disorders, supporting the functional importance of this residue (PMID: 10580070, 18795223). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000055999 SCV000087055 pathologic Dilated cardiomyopathy 1A 2013-09-19 no assertion criteria provided curation Converted during submission to Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057427 SCV000088541 not provided not provided no assertion provided not provided

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