ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.868G>A (p.Glu290Lys) (rs397517912)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000505709 SCV000855375 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000505709 SCV000292599 likely pathogenic not provided 2017-12-19 criteria provided, single submitter clinical testing The E290K variant in the LMNA gene has been reported previously in association with DCM, however, at least one of these patients also harbors another variant in a DCM-related gene (Pugh et al., 2014; Walsh et al., 2017; Hasselberg et al., 2017; Long et al., 2017). The E290K variant was also reported in a 34 year-old female with arrhythmia, and a strong family history of sudden cardiac death, however, molecular testing was not performed on the affected relatives (Finsterer et al., 2016). This variant has been observed in one other patient referred for cardiomyopathy genetic testing at GeneDx and was found to be apparently de novo in this individual. The E290K variant is not observed in large population cohorts (Lek et. al., 2016). The E290K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nonetheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000692291 SCV000820105 likely pathogenic Charcot-Marie-Tooth disease, type 2 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 290 of the LMNA protein (p.Glu290Lys). 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 observed in several individuals affected with dilated cardiomyopathy or conduction disease (PMID: 24503780, 29367541, 29095976, 27111165), and it has been observed to arise de novo in affected individuals (PMID: 29367541, Invitae). ClinVar contains an entry for this variant (Variation ID: 48090). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041376 SCV000065069 uncertain significance not specified 2012-07-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Glu290Lys v ariant in LMNA has not been reported in the literature and has not been identifi ed in large and broad populations by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). This low frequency is consistent with a disease caus ing role but insufficient to establish this with confidence. Computational analy ses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu290Lys variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. Although this data supports that the Glu290Lys variant may be pathogenic, additional studies are n eeded to fully assess its clinical significance.

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