Submissions for variant NM_000335.5(SCN5A):c.2314G>A (p.Asp772Asn)

gnomAD frequency: 0.00001  dbSNP: rs199473157

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041609	SCV000065305	uncertain significance	not specified	2015-09-16	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201502	SCV000256199	uncertain significance	Cardiomyopathy		criteria provided, single submitter	clinical testing
Invitae	RCV002223775	SCV000291791	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 772 of the SCN5A protein (p.Asp772Asn). This variant is present in population databases (rs199473157, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 23571586, 30193851, 33221895). ClinVar contains an entry for this variant (Variation ID: 48294). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 23571586, 32533946). 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.
Illumina Laboratory Services, Illumina	RCV001145375	SCV001306044	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145376	SCV001306045	uncertain significance	Progressive familial heart block, type 1A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145377	SCV001306046	uncertain significance	Sick sinus syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147315	SCV001308124	uncertain significance	Dilated cardiomyopathy 1E	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147316	SCV001308125	uncertain significance	Brugada syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147317	SCV001308126	uncertain significance	Long QT syndrome 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001841598	SCV001344275	uncertain significance	Cardiac arrhythmia	2023-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 772 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 718-938). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have reported conflicting results, with one study showing this variant has shorter inactivation time constants compared to wild type controls, and the other study showing the variant does not affect the sodium channel function (PMID: 23571586, 32268277). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085) and in an individual referred for Brugada testing (PMID: 20129283). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 5/249248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223775	SCV002503242	uncertain significance	not provided	2021-12-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224126	SCV003920452	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2022-07-25	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in six individuals with Brugada syndrome and one individual with Long QT syndrome (Kapplinger 2009 PMID:19716085; Kapplinger 2010 PMID:20129283; Walsh 2014 PMID:24136861; Berthome 2019 PMID:30193851; García-Molina 2019 PMID:30972196; Ciconte 2021 PMID:33221895). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.006% [1/15480]; https://gnomad.broadinstitute.org/variant/3-38587522-C-T?dataset=gnomad_r3), and in ClinVar (Variation ID:48294). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Multiple patch clamp studies have found that the functional properties associated with this variant do not differ from that of the wild-type allele (Crotti 2013 PMID:23571586; Glazer 2020 PMID:32533946). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058495	SCV000090015	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Blueprint Genetics	RCV000157485	SCV000207230	uncertain significance	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000041609	SCV000280467	uncertain significance	not specified	2015-09-14	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp772Asn (c.2314G>A) in SCN5A We have seen this variant in a patient with sick sinus syndrome and atrial standstill as well as a family history of sick sinus syndrome. Given the weak but suspicious case data, rarity in unselected cases and position in the channel, we consider this variant a variant of uncertain significance, suspicious to be disease causing and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in one patient referred for long QT genetic testing (phenotype unknown), one patient referred for Brugada genetic testing (phenotype unknown), one patient with dilated cardiomyopathy and AV block, and one case of intrauterine fetal demise. The variant is listed in ClinVar with conflicting classifications: pathogenic for long QT syndrome (Royal Brompton), variant of uncertain significance (Blueprint, LMM). Blueprint's ClinVar entry notes "Found together with likely pathogenic MYH7:NM_000257.2:c.709C>T". The variant was reported in one individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in other papers from the Ackerman group that use this cohort (ex. Kapa et al (2009), Giudicessi et al (2012).. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). The variant was also reported in a compendium of SCN5A variants seen in patients referred for Brugada syndrome genetic testing (Kapplinger et al 2010). Individual phenotypes were not reported and the authors note not all patients had evidence for Brugada. The variant was seen in a center in Nantes, France. Crotti et al (2013) observed the variant in one female caucasian fetus out of 91 unexplained intrauterine fetal deaths. Demise occurred at 35 weeks gestation. Per the LMM ClinVar data: "Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein." Per cardiodb.org variants in paralogue SCN3A and CACNA1H at the corresponding amino acid in have been associated with focal epilepsy (PMID 24157691) and childhood absent epilepsy (PMID 12891677), respectively. The variant is located in at the edge of a transmembrane domain. Ackerman's group has reported that the transmembrane spanning domains are enriched for variants seen with Brugada while the transmembrane segments (S3-5, S6) and DIID/DIV IDL are enriched for variants seen with long QT 3 (when compared to variants seen in controls) (Kapplinger et al 2015) The variant was reported online in 2 of 60,328 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 16th, 2015). Specifically, the variant was observed in 1 of 8374 South Asian individuals and 1 of 33,351 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).