ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1039G>A (p.Glu347Lys) (rs267607548)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057216 SCV000234692 likely pathogenic not provided 2016-03-24 criteria provided, single submitter clinical testing The E347K likely pathogenic variant in the LMNA gene has been reported in one individual with cardiac conduction defects (CCD) as well as in several other similarly affected family members; cardiomyopathy was not evident in these individuals (Vytopil et la., 2003). E347K was also reported in one individual with DCM and arrhythmia who also harbored the R331Q variant in LMNA (Benedetti et al., 2007). E347K was not observed in 200 published control alleles (Vytopil et al., 2003) and approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E347K 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. This substitution is located in the Coil 2B region and occurs at a position that is conserved across species (Bollati et al., 2012). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function; however, two in silico models predict this variant is damaging to the protein structure/function and crystalization studies predict the E347K variant impacts protein stability and may result in incorrect assembly of intermediate filaments (Bollati et al., 2012; Gangemi et al., 2013).Therefore, this variant is likely pathogenic
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057216 SCV000088329 not provided not provided no assertion provided not provided

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