ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2893C>T (p.Arg965Cys) (rs199473180)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000058533 SCV000259529 uncertain significance Brugada syndrome 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 965 of the SCN5A protein (p.Arg965Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473180, ExAC 0.04%). This variant has been observed in individual(s) with Brugada syndrome or referred for Brugada syndrome testing (PMID: 24524602, 23293604, 23321620, 11901046), in individual(s) referred for long QT syndrome testing (PMID: 23631430) and in an individual with long QT syndrome (PMID: 24762593). However, in that individual a pathogenic allele was also identified in KCNH2, which suggests that this c.2893C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 67763). Experimental studies have shown that this variant affects SCN5A protein function (PMID: 19272188). 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 RCV000825044 SCV000966243 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg965Cys variant in SCN5A has been reported in at least 11 individuals: 7 with Brugada s yndrome, 1 with arrhythmogenic right ventricular cardiomyopathy (ARVC) and 3 wit h long QT syndrome, one of whom also carried a variant in a different gene that may explain the long QT phenotype (Priori 2000, Priori 2002, Hsueh 2009, Kapplin ger 2010, Duthoit 2012, Lieve 2013, Sommariva 2013, Jimmy 2014, Mellor 2017). Ad ditionally, this variant reportedly segregated with disease in one affected rela tive (ClinVar: SCV000280471.1). In vitro functional studies provide some evidenc e that the p.Arg965Cys variant may impact protein function (Hsueh 2009). This va riant has also been identified in 10/17136 of East Asian chromosomes by gnomAD ( Computational prediction tools and conservati on analysis suggest that the p.Arg965Cys variant may impact the protein. Additio nally, two other missense changes in this codon (p.Arg965His and p.Arg965Leu) ha ve been identified in patients with Brugada syndrome and/or Long QT syndrome, ra ising the possibility that changes at this position may not tolerated (Meregalli 2006, Kapplinger 2009 and 2010, Amin 2011, Hoshi 2014). However, the clinical s ignificance of these changes is uncertain. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of the p.Arg965Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PP3, PS3_Supporting.
Mendelics RCV000987214 SCV001136463 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000183015 SCV001248652 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001178586 SCV001343063 uncertain significance Arrhythmia 2020-05-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 965 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant may affect inactivation of the sodium channel (PMID: 19272188). However, clinical relevance of this observation is unknown. This variant has been reported in seven individuals affected with Brugada syndrome (PMID: 11076825, 11901046, 20129283, 23293604, 23321620) and a family with a complex familial arrhythmia syndrome (Lin et al 2019 DOI: 10.1101). This variant has been identified in 16/246378 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058533 SCV000090053 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11076825;PMID:11901046;PMID:19272188;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183015 SCV000280471 likely pathogenic not provided 2015-06-12 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. SCN5A: p.Arg965Cys (c.2893C>T). See in a family with Brugada syndrome in our center with segregation in an affected first degree relative. We currently (4/27/2012) classify it as likely disease causing, based on the data reviewed below. In total the variant has been seen in ~4 unrelated individuals with Brugada syndrome, not including the patient's family. Priori et al (2000, 2002) reported observing this variant in a 30yo male with Brugada Syndrome who received an appropriate shock while sleeping (Priori et al 2002). Ancestry was not reported, though the cohort was recruited in Europe. Hsueh et al (2009) observed p.Arg965Cys in an individual with Brugada syndrome from Taiwan who had a history of ventricular fibrillation arrest. The variant was listed as observed in three unrelated individuals in a multi-center published compendium of SCN5A variants (Kapplinger et al 2010). These three cases were contributed by the Brugada group, Paris, and PGxHealth (now Transgenomics). The case from the Brugada group may very well be the patient's family, while the other two cases are likely unique. No segregation data was provided in these reports, though we do have some weak segregation data in the patient's family with both the patient and his brother having this variant and phenotypic evidence of Brugada syndrome. GeneDx gave me a verbal update on 4/27/2012 that they have seen this variant in one other individual, a 5 year old Caucasian male tested with their long QT panel, but with diagnosis not reported. Variants affecting the same codon (p.Arg965His and p.Arg965Leu) and surrounding codons (p.Gln960Lys and p.Arg971Cys) have been reported in association with Brugada and LQT syndromes. The variant occurs in the interdomain cytoplasmic linkers DII-DIII. Hsueh et al (2009) studied the in vitro phenotype using patch clamp assays and reported that the steady state inactivation was shifted to a more negative potential with slower recovery from inactivation. This non-conservative amino acid substitution replaces a polar, positive Arginine codon with a neutral Cysteine. Polyphen2 predicts the variant to be probably damaging. The Arginine at codon 965 is conserved across species. In total, the variant has not been observed in ~7024 control or general population samples studied, with less than 100 of these samples matching the patient's Asian ancestry (though the majority of the samples match the ancestry of several of the reported cases). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5300 Caucasian and African American individuals (as of 4/27/2012). A different variant at the same codon (p.Arg965Gly) as observed in 1/3419 Caucasians and 0/1706 African-American individuals in this dataset. There is no variation at codon 965 in the 24 Asian individuals in the NIEHS EGP dataset (as of 4/27/2012). Priori et al (2002) did not observe it in 400 control individuals (likely European ancestry). The variant is not currently listed in dbSNP or 1000 genomes (4/27/2012). Hsueh et al (2009) did not report control data. Kapplinger et al (2010) note the variant was not observed in 1300 population controls of varying ancestries.
Clinical Genetics,Academic Medical Center RCV000183015 SCV001924589 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000183015 SCV001955483 pathogenic not provided no assertion criteria provided clinical testing

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