ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4783G>A (p.Asp1595Asn) (rs137854607)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183084 SCV000235494 pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing The D1595N pathogenic variant in the SCN5A gene has been reported to co-segregate with atrioventricular conduction block in two siblings and a parent (Wang et al., 2002). In this same paper, functional studies of D1595N using a whole-cell patch clamp technique identified a combination of biophysical abnormalities expected to slow myocardial conduction velocity (Wang et al., 2002). D1595N results in a semi-conservative amino acid substitution at a position that is completely conserved across species. In addition, a different missense variant in the same residue (D1595H) is classified as pathogenic by GeneDx and has also been reported in association with DCM (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Finally, the D1595N pathogenic variant 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. In summary, D1595N in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000469185 SCV000545100 pathogenic Brugada syndrome 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1595 of the SCN5A protein (p.Asp1595Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with atrioventricular conduction (AV) block in a family (PMID: 11804990) and has been observed in individuals affected with cardiac conduction system defects (Invitae). ClinVar contains an entry for this variant (Variation ID: 9385). This variant disrupts the p.Asp1595 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15671429, 18048769). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been shown to affect SCN5A protein function (PMID: 11804990). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009983 SCV000030204 pathogenic Progressive familial heart block, type 1A 2002-01-22 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058705 SCV000090225 not provided Atrioventricular block no assertion provided literature only This variant has been reported as associated with Atrioventricular conduction block in the following publications (PMID:11804990). 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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