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

gnomAD frequency: 0.00018  dbSNP: rs45553235

Total submissions: 26

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, Mass General Brigham 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058479	SCV000291789	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618520	SCV000736202	likely benign	Cardiovascular phenotype	2021-11-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001842310	SCV000913721	likely benign	Cardiac 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	RCV000058479	SCV001160294	uncertain significance	not provided	2023-08-09	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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001149798	SCV001310793	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001149800	SCV001310795	benign	Sick sinus 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). 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 Laboratory Services, 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 Laboratory Services, 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.
Baylor Genetics	RCV001149802	SCV001521124	uncertain significance	Long QT syndrome 3	2020-11-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151790	SCV003922456	likely benign	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2074C>A (p.Gln692Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 248922 control chromosomes. The observed variant frequency is approximately 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no penetrant association of c.2074C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
Dept of Medical Biology, Uskudar University	RCV000148842	SCV004022003	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP2, BS1
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV001149802	SCV004101824	uncertain significance	Long QT syndrome 3	2023-10-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486632	SCV004239657	likely benign	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058479	SCV004701400	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SCN5A: PM2:Supporting
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058479	SCV001958417	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058479	SCV001971002	likely benign	not provided		no assertion criteria provided	clinical testing