ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1921A>G (p.Ser641Gly) (rs76649554)

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Total submissions: 6
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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 RCV000058181 SCV000050692 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000058181 SCV000234203 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing The S981G variant was first reported in one individual from a cohort of over 1,300 ostensibly healthy control individuals (Kapa et al., 2009). It was subsequently reported in another individual from a cohort of individuals who underwent exome sequencing who were not selected for cardiomyopathy, arrhythmia, or a family history of sudden cardiac death (Ng et al., 2013). The S981G variant was also observed in two individuals diagnosed with hypertrophic cardiomyopathy (Lopes et al., 2015), and in one individual from a cohort of over 2,200 individuals recruited for non-antiarrhythmic drug exposure phenotypes who underwent pharmacogenomic testing (Van Driest et al., 2016). In all of these published cases, no further clinical details, segregation studies or follow-up cardiac evaluations for arrhythmia were reported. The S981G variant has been observed both independently, and in conjunction with additional cardiogenetic variants, in multiple individuals referred for LQTS genetic testing at GeneDx. However, observation in these individuals, for whom informative segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant.While the S981G variant was observed in approximately 0.12% of alleles from individuals of South Asian ancestry in the Exome Aggregation Consortium, it was not observed with any significant frequency in the 1000 Genomes Project, or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S981G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, however, Glycine is tolerated at this position in at least three non-mammalian species. Finally, 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 pathogenic or rare benign.
Invitae RCV000470125 SCV000555895 likely benign Long QT syndrome 2016-12-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621297 SCV000736421 uncertain significance Cardiovascular phenotype 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000776201 SCV000911333 uncertain significance Arrhythmia 2018-08-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 74/271220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058181 SCV000089701 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300).

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