ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2074C>A (p.Gln692Lys) (rs45553235)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148842 SCV000050722 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151790 SCV000200244 likely benign not specified 2017-05-22 criteria provided, single submitter clinical testing This variant is present in gnomAD: 0.29% (29/10130 AJ). This frequency is too hi gh for SCN5A-associated disorders. Glutamine (Gln) at position 692 is poorly c onserved in evolution and several species (including 1 mammal) carry the variant amino acid (Lys), suggesting that this change may be tolerated. Additional comp utational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein.
GeneDx RCV000151790 SCV000235400 uncertain significance not specified 2017-03-16 criteria provided, single submitter clinical testing The Q692K variant of uncertain significance in the SCN5A gene has been previously reported in association with multiple phenotypes (van Langren et al., 2003; Chung et al., 2007; Millat et al., 2009; Lopes et al., 2015). van Langren et al (2003) identified Q692K in a patient of Turkish ancestry who suffered sudden unexplained death during sleep at age 14, and who also harbored the R562M variant in the KCNQ1 gene; both variants were reported to be paternally inherited (van Langen et al., 2003). The Q692K variant has also been reported in a 10 year-old male with aborted sudden cardiac death and a prolonged QTc interval (Chung et al., 2007). Additionally, Millat et al. (2009) identified this variant in a patient who passed away from SIDS, but no segregation studies were performed. A patient with HCM was found to harbor Q692K, but no other clinical information was provided (Lopes et al., 2015). Nevertheless, Q692K has also been reported in apparently healthy individuals (Ackerman et al., 2004; Kapa et al., 2009; Ghouse et al., 2015; Kapplinger et al., 2015), and is classified in ClinVar as a variant of uncertain significance by two other clinical laboratories (SCV000200244.3, SCV000291789.1; Landrum et al., 2016). The Q692K variant was observed in approximately 0.02-0.10% of alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project, and the Exome Aggregation Consortium (ExAC). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for LQTS, Arrhythmia, or Cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The Q692K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202895 SCV000257778 uncertain significance Brugada syndrome 1; Long QT syndrome 3 2015-04-12 criteria provided, single submitter clinical testing
Invitae RCV000157484 SCV000291789 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618520 SCV000736202 likely benign Cardiovascular phenotype 2018-08-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other data supporting benign classification
Color RCV000777757 SCV000913721 likely benign Arrhythmia 2018-06-05 criteria provided, single submitter clinical testing
Mendelics RCV000987217 SCV001136466 benign Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000151790 SCV001160294 uncertain significance not specified 2019-03-02 criteria provided, single submitter clinical testing The SCN5A c.2074C>A; p.Gln692Lys variant (rs45553235; ClinVar Variation ID: 67712) has been previously reported in multiple individuals evaluated for sudden cardiac death (SCD) with a diagnosis of long QT syndrome (Van Langen 2003, Tan 2005, Hofman 2007, Chung 2007), sudden infant death syndrome (SIDS; Millat 2009), and hypertrophic cardiomyopathy HCM (Lopes 2015 and Bottillo 2016). However, co-segregation of this variant with any of these phenotypes has not been demonstrated in affected family members, and in once case was shown to have been inherited from the proband's unaffected father (Van Langen 2003). Moreover, multiple studies have noted the relatively high allele frequency of this variant in various healthy populations (Ackerman 2004, Kapa 2009, Kapplinger 2010) and the general population (Bottillo 2016, Refsgaard 2012, Andreasen 2013, Dorschner 2013, Amendola 2015, Ng 2013). For instance, this variant is found in the Genome Aggregation Database with an allele frequency in Ashkenazi Jewish individuals of 0.26% (27/10334 alleles). Additionally, at least one study has identified this variant in an adult Danish individual who had a QT interval within the normal range (Ghouse 2015). The glutamine at codon 692 is moderately conserved (Alamut software v2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Nonetheless, based on the available information, the clinical significance of this variant is uncertain. References: Ackerman et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm. 2004 Nov;1(5):600-7. Amendola LM et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. Andreasen C et al. Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data. Can J Cardiol. 2013 Sep;29(9):1104-9. Bottillo et al. Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. Gene. 2016 Feb 15;577(2):227-35. Chung SK et al. Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm. 2007 Oct;4(10):1306-14. Dorschner MO et al. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013 Oct 3;93(4):631-40. Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hofman N et al. Contribution of inherited heart disease to sudden cardiac death in childhood. Pediatrics. 2007 Oct;120(4):e967-73. Kapa et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kapplinger et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Millat G et al. Contribution of long-QT syndrome genetic variants in sudden infant death syndrome. Pediatr Cardiol. 2009 May;30(4):502-9. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Refsgaard L et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012 Aug;20(8):905-8. Tan HL et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. 2005 Jul 12;112(2):207-13. Van Langen et al. The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. J Med Genet. 2003 Feb;40(2):141-5.
Illumina Clinical Services Laboratory,Illumina RCV000987217 SCV001309128 uncertain significance Brugada syndrome 1 2019-02-21 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 Clinical Services Laboratory,Illumina RCV001149798 SCV001310793 uncertain significance Paroxysmal familial ventricular fibrillation 1 2019-02-21 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 Clinical Services Laboratory,Illumina RCV001149799 SCV001310794 uncertain significance Dilated cardiomyopathy 1E 2019-02-21 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 Clinical Services Laboratory,Illumina RCV001149800 SCV001310795 benign Sick sinus syndrome 1, autosomal recessive 2019-02-21 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001149801 SCV001310796 uncertain significance Progressive familial heart block, type 1A 2019-02-21 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 Clinical Services Laboratory,Illumina RCV001149802 SCV001310797 likely benign Long QT syndrome 3 2019-02-21 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058479 SCV000089999 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:12566525;PMID:15851227;PMID:17905336;PMID:19841300;PMID:20129283;PMID:22378279).
CSER _CC_NCGL, University of Washington RCV000148842 SCV000190583 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000157484 SCV000207229 likely benign Brugada syndrome 2014-10-06 no assertion criteria provided clinical testing

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