ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2079_2089del (p.Pro694fs) (rs794728466)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182006 SCV000234309 likely pathogenic not provided 2017-07-24 criteria provided, single submitter clinical testing Although the c.3099_3109del11 likely pathogenic variant in the KCNH2 gene has not been reported to ourknowledge, this variant causes a shift in reading frame starting at codon proline 1034, changing it to an arginine, andcreating a premature stop codon at position 81 of the new reading frame, denoted p.P1034RfsX81. This likelypathogenic variant is expected to result in an abnormal, truncated protein product. Several other downstream latetermination variants have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore,c.3099_3109del11 has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium etal., 2015; Exome Variant Server).Therefore, the c.3099_3109del11 variant in the KCNH2 gene is likely pathogenic.
Invitae RCV000702086 SCV000830920 uncertain significance Long QT syndrome 2018-03-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the KCNH2 gene (p.Pro1034Argfs*81). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acids of the KCNH2 protein. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200697). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182006 SCV000924808 likely pathogenic not provided 2017-07-06 no assertion criteria provided provider interpretation p.Pro1034ArgfsX81 (P1034RfsX81; c.3099_3109del11) in the KCNH2 gene (NM_000238.2) Based on the evidence reviewed below, we classify it as likely disease causing, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The KCNH2 gene (also known as HERG) encodes potassium channel, voltage-gated, subfamily H, member 2 protein. It plays an essential role in the final repolarization of the ventricular action potential (Gianulis and Trudeau, 2011). This specific mutation in the KCNH2 gene has not been previously reported in the literature, according to GeneDx and to a search of PubMed and Google. However, it has been seen in one presumably unrelated individual tested for LQTS at GeneDx. We also have a SCICD patient with a similar frameshift mutation beginning at Pro1034 in KCNH2 (p.Pro1034fs; c.3095_3099dup4). This variant was interpreted on August 26, 2011, by genetic counselor Colleen Caleshu of the Stanford Center for Inherited Cardiovascular Disease. Familion classified this as a novel Class I variant. There was moderate segregation data from within this family: It co-segregated with LQTS in four affected individuals including the patient, her daughter, her brother and her father. Familion reported that they did not see the variant in 1300 presumably healthy individuals of mixed ancestry (published in Kapa et al. 2009). Taken together, these data strongly support this variant as the cause of LQTS in this patient and her family. Furthermore, this variant is of a type frequently seen to cause disease. c.3099_3109del11 creates a shift in reading frame starting at codon 1034, changing it from a proline to an arginine and creating a premature stop codon at position 81 of the new reading frame. This is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple frameshift mutations in the KCNH2 gene have been reported in individuals with LQTS (GeneDx references the Human Gene Mutation database: Stenson et al. 2003). Some of these frameshift mutations begin specifically at Pro1034 or nearbyresidues: p.Pro1034fs+18X (Kapplinger et al. 2009), p.Pro1034fx+21X (Kapplinger et al. 2009), p.Pro1034fx+83X (Kapplinger et al. 2009), p.Gly1031fs+86X (Napolitano et al. 2005), p.Gly1031fs+20X (Napolitano et al. 2005), p.Gly1031fs+24X (Splawski et al. 2000), p.Arg1032fs (Millat et al. 2006), p.Arg1033fs+22X (Napolitano et al. 2005), p.Arg1033fs+23X (Kapplinger et al. 2009), p.Arg1033fs+82X (Kapplinger et al. 2009) etc. This is not an exhaustive list. The variant is not present in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The coverage at this site is ~34x in exomes and ~30x in genomes.

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