ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2314G>A (p.Asp772Asn) (rs199473157)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157485 SCV000207230 uncertain significance Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing
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.
Invitae RCV000229288 SCV000291791 uncertain significance Brugada syndrome 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 772 of the SCN5A protein (p.Asp772Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs199473157, ExAC 0.006%). This variant has been reported in one individual referred for long QT syndrome testing (PMID: 19716085), one individual referred for Brugada testing (PMID: 20129283), and one case of intrauterine death (PMID: 23571586). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 48294). This variant identified in the SCN5A gene is located in the transmembrane spanning DII-S2/S3 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change slightly affects SCN5A current, but clinical significance of this is uncertain (PMID: 23571586). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare 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
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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.