Submissions for variant NM_000335.5(SCN5A):c.2865_2866del (p.Glu955fs)

dbSNP: rs756159737

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482288	SCV000566378	likely pathogenic	not provided	2021-05-13	criteria provided, single submitter	clinical testing	Has been reported as likely pathogenic in an individual with Brugada syndrome in published literature (Campuzano et al., 2020), and in individuals tested at GeneDx; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 418944; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32268277)
Invitae	RCV000482288	SCV000637109	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu955Aspfs*74) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (rs756159737, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 418944). For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853446	SCV000996357	uncertain significance	Sudden cardiac death; Prolonged QT interval	2019-04-02	criteria provided, single submitter	research	The SCN5A Glu955Aspfs*74 variant has not been previously reported in literature but has been identified in individuals with Brugada Syndrome and Restrictive Cardiomyopathy (GeneDx, Pers Comm.; Invitae, Pers Comm.). It is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000016, and highest sub-population frequency is 0.0035%. We identified this variant in proband diagnosed with both LongQT and infranodal conduction system disease, however this variant did not segregate to an affected family member. Based on these findings we cannot disregard the SCN5A variant. We classify the SCN5A Glu955Aspfs*74 as uncertain significance. Given the gnomAD frequency, this may be further downgraded in future.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841395	SCV001361006	likely pathogenic	Cardiac arrhythmia	2019-12-24	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2865_2866delGA (p.Glu955AspfsX74) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 248468 control chromosomes. To our knowledge, no occurrence of c.2865_2866delGA in individuals affected with Arrhythmia/Brugada/Long QT syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (one each as Pathogenic, Likely pathogenic and VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002436529	SCV002745888	pathogenic	Cardiovascular phenotype	2017-08-31	criteria provided, single submitter	clinical testing	The c.2865_2866delGA pathogenic mutation, located in coding exon 16 of the SCN5A gene, results from a deletion of two nucleotides at nucleotide positions 2865 to 2866, causing a translational frameshift with a predicted alternate stop codon (p.E955Dfs*74). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.