ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1106T>C (p.Leu369Pro) (rs397517886)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041305 SCV000064997 likely pathogenic Primary dilated cardiomyopathy 2011-06-02 criteria provided, single submitter clinical testing The Leu369Pro variant has not been reported in the literature. Our laboratory ha s detected this variant in one individual with DCM and conduction system disease , which is typical for LMNA variants.Parental testing revealed de novo occurrenc e, which strongly supports a pathogenic role. In addition, leucine (Leu) at pos ition 369 is conserved in evolutionary distant species and three computer tools (AlignGVGD, Polyphen2, SIFT) predict this change to be deleterious although thei r accuracy has not been clinically validated. In summary, de novo occurrence, co mputer predictions and clinical data support a pathogenic role.
GeneDx RCV000236658 SCV000293083 uncertain significance not specified 2015-09-02 criteria provided, single submitter clinical testing The L369P variant was previously reported in a patient with dilated cardiomyopathy; however, segregation studies were not completed (Pugh et al., 2014). It was not observed in 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 L369P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. This substitution occurs at a position that is conserved across species; however, Proline has been observed in evolution. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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