ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1755dup (p.Pro586fs) (rs794728455)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181993 SCV000234296 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The c.2775dupG pathogenic variant in the KCNH2 gene has been published in association with LQTS (Splawski et al., 2000; Nof et al., 2010; Zarraga et al., 2011). This variant causes a shift in reading frame starting at codon proline 926, changing it to an alanine, and creates a premature stop codon at position 14 of the new reading frame, denoted p.Pro926AlafsX14. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Splawski et al. (2000) initially identified the c.2775dupG pathogenic variant in one individual diagnosed with LQTS. Subsequently, Nof et al. (2010) detected this variant in trans with the K897T polymorphism in an infant with ventricular tachycardia in utero and sudden death at 2 days of life. The c.2775dupG pathogenic variant was maternally inherited and also identified in a sibling, both were mildly affected. In vitro functional analysis showed an exaggerated deleterious effect on channel function when in trans with the K897T polymorphism, explaining the more severe presentation in the infant. Following this report, the c.2775dupG pathogenic variant was found to segregate with a LQTS phenotype in a large family (Zarraga et al., 2011). Furthermore, mRNA and immunoblot studies showed significantly reduced product, suggesting nonsense-mediated decay, and in vitro analysis corroborated a damaging effect to channel function (Zarraga et al., 2011). This pathogenic variant has been observed in multiple other unrelated individuals referred for LQTS genetic testing at GeneDx. Lastly, this variant is not observed in large population cohorts (Lek et al., 2016). In summary, c.2775dupG in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000204205 SCV000260323 pathogenic Long QT syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 12 of the KCNH2 mRNA (c.2775dupG), causing a frameshift at codon 926. This creates a premature translational stop signal (p.Pro926Alafs*14) and is expected to result in an absent or disrupted protein product. Truncating variants in KCNH2 are known to be pathogenic. This particular truncation has been reported in the literature and has been shown to segregate with long QT syndrome in several families and individuals (PMID: 10973849, 20181576, 21419236). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000249424 SCV000319786 pathogenic Cardiovascular phenotype 2018-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
OMIM RCV000015520 SCV000035785 pathogenic Long QT syndrome 2 2006-09-01 no assertion criteria provided literature only
OMIM RCV000015521 SCV000035786 pathogenic Long QT syndrome 1/2, digenic 2006-09-01 no assertion criteria provided literature only

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