ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.551GCGCGGGCG[3] (p.Gly189_Ala190insGlyAlaGly)

dbSNP: rs551056698
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000691109 SCV000818852 uncertain significance Long QT syndrome 2023-12-01 criteria provided, single submitter clinical testing This variant, c.560_568dup, results in the insertion of 3 amino acid(s) of the KCNH2 protein (p.Gly187_Gly189dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs794728421, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 200604). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
New York Genome Center RCV004799192 SCV001432926 uncertain significance Short QT syndrome type 1; Long QT syndrome 2 2022-01-07 criteria provided, single submitter clinical testing
GeneDx RCV001580465 SCV001817787 uncertain significance not provided 2022-10-04 criteria provided, single submitter clinical testing Reported in a male diagnosed with LQTS at birth who developed atrial fibrillation at four years of age; however, he also harbored other variants in the SCN5A gene (Johnson et al., 2008); denoted INS GCGCGGGCG 569570 or INS GAG 189190 due to alternate nomenclature; Reported in a control individual with a QTc of 367 milliseconds and no history of cardiac arrhythmia (Paulussen et al., 2000); In-frame duplication of 3 amino acids in a non-repeat region; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10790218, 18452873)
Ambry Genetics RCV002345631 SCV002648875 uncertain significance Cardiovascular phenotype 2024-01-03 criteria provided, single submitter clinical testing The c.560_568dupGCGCGGGCG variant (also known as p.G187_G189dup) is located in coding exon 4 of the KCNH2 gene. This variant results from an in-frame duplication of GCGCGGGCG at nucleotide positions 560 to 568. This results in the insertion of three amino acid residues (glycine, alanine, and glycine) between codons 187 and 189, located in the N-terminal, cytoplasmic region of the protein. This variant has been detected in conjunction with an SCN5A variant in an individual with prolonged QT interval and atrial fibrillation, and has also been detected in a control individual with normal QTc interval (Paulussen A et al. Hum. Mutat., 2000 May;15:483; Johnson JN et al. Heart Rhythm, 2008 May;5:704-9). These amino acid positions are not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genomics Laboratory, Washington University in St. Louis RCV003454480 SCV004177087 uncertain significance Long QT syndrome 2 2023-10-17 criteria provided, single submitter clinical testing The KCNH2 c.560_568dup (p.Gly187_Gly189dup) variant has been reported in conjunction with an SCN5A variant in one individual affected with prolonged long QT interval and atrial fibrillation (Johnson JN et al., PMID: 18452873). It has also been observed in a control individual with a normal Qtc interval (Paulussen A et al., PMID: 10790218). This variant is only observed on 1/15,326 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant is predicted to cause a change in the length of the protein due to an in-frame duplication of three amino acids in a repetitive region without a known function. This variant has been reported in the ClinVar database as a variant of uncertain significance by four submitters for a cardiovascular phenotype and one submitter for seizures (ClinVar Variation ID: 200604). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Breakthrough Genomics, Breakthrough Genomics RCV001580465 SCV005195729 uncertain significance not provided criteria provided, single submitter not provided
GeneDx RCV001842842 SCV000234262 uncertain significance Cardiac arrhythmia 2014-07-15 flagged submission clinical testing c.560_568dupGCGCGGGCG; p.Gly187_Gly189dup in exon 4 of the KCNH2 gene (NM_000238.2). The normal sequence with the bases that are duplicated in braces is GGGCG{GCGCGGGCG}CCCCG.The c.560_568dupGCGCGGGCG variant in the KCNH2 gene has been reported in one individual with congenital LQTS and atrial fibrillation (Johnson J et al., 2008). The c.560_568dupGCGCGGGCG variant results in an in-frame duplication of three amino acids. Mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change.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).

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