ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5624T>C (p.Met1875Thr) (rs199473324)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183128 SCV000235539 likely pathogenic not provided 2016-06-27 criteria provided, single submitter clinical testing The Met1875Thr mutation in the SCN5A gene has been reported in association with atrial fibrillation in multiple individuals from three generations of a Japanese family (Makiyama T et al., 2008). Six individuals had frequent premature atrial contractions (PACs) or atrial fibrillation, and only one individual had a prolonged QTc interval. Met1875Thr was absent from 210 Japanese control individuals in this study (Makiyama T et al., 2008). In addition, Met1875Thr was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Met1875Thr results in a non-conservative amino acid substitution of a non-polar Methionine with a polar Threonine at a position that is highly conserved across species (Makiyama T et al., 2008). Mutations in nearby residues (Val1861Ile, Lys1872Asn, Arg1897Trp) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. Functional studies showed a pronounced depolarized shift in steady-state inactivation and no persistent inward sodium currents, which is consistent with a unique gainof- function type of modulation (Makiyama T et al., 2008).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058796 SCV000090316 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18929244). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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