ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.224C>T (p.Ser75Phe) (rs879253975)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236603 SCV000293014 likely pathogenic not provided 2018-02-26 criteria provided, single submitter clinical testing The S75F variant in the LMNA gene has been reported previously in association with DCM, however no additional clinical or segregation information was provided (Haas et al., 2015). 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 S75F 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. Additionally, this substitution occurs at a position where only amino acids with similar properties to Serine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R72C, R72L, K78E, E82K) 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. Based on currently available evidence, S75F is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.

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