ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.3247A>G (p.Thr1083Ala)

gnomAD frequency: 0.00003  dbSNP: rs751559990
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181914 SCV000234217 uncertain significance not provided 2014-04-15 criteria provided, single submitter clinical testing p.Thr1083Ala (ACC>GCC): c.3247 A>G in exon 14 of the KCNH2 gene (NM_000283.2). A variant of unknown significance has been identified in the KCNH2 gene. The T1083A variant has not been published as a mutation or as a benign polymorphism to our knowledge. The T1083A variant was not observed 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 T1083A 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. Missense mutations in nearby residues (Y1078C, P1093L) have been reported in association with LQTS, supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV001045529 SCV001209388 uncertain significance Long QT syndrome 2022-05-21 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 200529). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is present in population databases (rs751559990, gnomAD 0.03%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1083 of the KCNH2 protein (p.Thr1083Ala).
Color Diagnostics, LLC DBA Color Health RCV001842837 SCV001346128 uncertain significance Cardiac arrhythmia 2023-12-05 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 suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact 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 8/242348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics RCV002321715 SCV002609489 uncertain significance Cardiovascular phenotype 2021-11-29 criteria provided, single submitter clinical testing The p.T1083A variant (also known as c.3247A>G), located in coding exon 14 of the KCNH2 gene, results from an A to G substitution at nucleotide position 3247. The threonine at codon 1083 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002485200 SCV002792604 uncertain significance Short QT syndrome type 1; Long QT syndrome 2 2021-09-20 criteria provided, single submitter clinical testing

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