ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1189C>T (p.Arg397Cys) (rs374726751)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000726799 SCV000927803 likely pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726799 SCV000703110 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000194852 SCV000247851 uncertain significance not specified 2015-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000194852 SCV000917594 uncertain significance not specified 2018-04-19 criteria provided, single submitter clinical testing Variant summary: LMNA c.1189C>T (p.Arg397Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 275346 control chromosomes. This frequency is lower than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (2.5e-05 vs 0.0001), allowing no conclusion about variant significance. The c.1189C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and laminopathy. These reports do not provide unequivocal conclusions about an association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000535613 SCV000657793 uncertain significance Charcot-Marie-Tooth disease, type 2 2017-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 397 of the LMNA protein (p.Arg397Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs374726751, ExAC 0.01%). This variant has been reported in 2 individuals affected with dilated cardiomopathy (DCM) and 3 individuals with unspecified cardiac disease (PMID: 23062543, 23183350). ClinVar contains an entry for this variant (Variation ID: 211387). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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