ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.250G>A (p.Glu84Lys) (rs794728602)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621704 SCV000737171 uncertain significance Cardiovascular phenotype 2017-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000758164 SCV000882829 likely pathogenic Primary dilated cardiomyopathy 2019-02-12 criteria provided, single submitter research The c.250G>A (p.E84K) variant is present in dbSNP database, however, clinical significance is controversial - it was previously classified as pathogenic and as variant of unknown clinical significance. To our knowledge, the c.250G>A (p.E84K) was first described by Wilde et al. (2014). He observed three unrelated families with heterozygous carriers manifesting at their 40s with heart rhythm disturbances and progressing in DCM. We observed a family with both homozygous and heterozygous carriers; notably, 2 homozygous carriers demonstrated severe clinical features and manifested with progressive heart failure and DCM in young age. Heterozygous carriers had no complaints, but all of them were younger than 40. Family denied consanguineous marriage. Because of previously described effect of c.250G>A (p.E84K) variant in heterozygous state and severe clinical feature in homozygous carriers, we assume that this variant may demonstrate codominant features. The c.250G>A (p.E84K) variant was also absent in large population databases. Multiple lines of computational evidence predict a deleterious effect of c.250G>A (p.E84K) variant on gene or gene product. Also, LMNA gene has low rate of benign missense variants. In summary, frequency data, computational evidence and family segregation data are present, and we consider the c.250G>A (p.E84K) variant meets criteria for likely pathogenic variants.

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