ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2074C>A (p.Gln692Lys) (rs45553235)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618520 SCV000736202 likely benign Cardiovascular phenotype 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148842 SCV000050722 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000157484 SCV000207229 likely benign Brugada syndrome 2014-10-06 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148842 SCV000190583 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
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).
Color RCV000777757 SCV000913721 likely benign Arrhythmia 2018-06-05 criteria provided, single submitter clinical testing
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
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.
Invitae RCV000157484 SCV000291789 likely benign Brugada syndrome 2018-01-19 criteria provided, single submitter clinical testing
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.

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