ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5065G>A (p.Asp1689Asn) (rs1060499900)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532378 SCV000637169 uncertain significance Brugada syndrome 2017-07-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1690 of the SCN5A protein (p.Asp1690Asn). 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 reported in individuals affected with Brugada syndrome (PMID: 23085483, 27108952). This variant has been observed in individual with Brugada syndrome (PMID: 26173111) who was also reported to have a pathogenic allele in SCN5A, which suggests that this c.5068G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 403420). This variant identified in the SCN5A gene is located in the transmembrane spanning DIV-S5/S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Experimental studies have shown that this missense change affects trafficking of the channel to the membrane, reduces peak sodium channel current density and causes a positive shift in stead-state activation potential in vitro (PMID: 23085483, 27108952). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455733 SCV000540273 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Functional study suggests pathogenicity, but no segs and only 1 proband; Absent from ExAC

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