7-150948861-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.2587C>T(p.Arg863*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000238.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2587C>T | p.Arg863* | stop_gained | 10/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2587C>T | p.Arg863* | stop_gained | 10/15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1567C>T | p.Arg523* | stop_gained | 6/11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3420C>T | non_coding_transcript_exon_variant | 8/13 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251266Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135820
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2021 | Reported multiple times in association with LQTS (Van Langen et al., 2003; Nagaoka et al., 2008; Kapa et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant failed to form functional KCNH2 channels (Teng et al., 2004; Akhavan et al., 2005; Yao et al., 2009); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 220208; ClinVar); This variant is associated with the following publications: (PMID: 15840476, 21143190, 19716085, 25525159, 24993425, 24366185, 14714110, 18441445, 19841300, 15961404, 19324319, 12566525, 22515331) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2016 | - - |
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 220208). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 12566525, 14714110, 15840476, 22515331). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs773724817, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg863*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 28, 2022 | Variant summary: KCNH2 c.2587C>T (p.Arg863X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.9e-06 in 254304 control chromosomes (gnomAD). c.2587C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome (examples: Van Langen_2003, Teng_2004, Kapa_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Teng_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Congenital long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2020 | The p.Arg863X variant in KCNH2 has been reported in 3 individuals with Long QT syndrome (LQTS), including a presumed de novo occurrence, and in 1 individual referred for LQTS testing (Teng 2004 PMID: 14714110, Yao 2009 PMID: 19324319, Tester 2005 PMID: 15840476, Van Langen 2003 PMID: 12566525, Zamorano-Leon 2012 PMID: 22515331). This variant segregated with LQTS in 5 relatives from 1 family (Teng 2004 PMID: 14714110). It has also been reported by other clinical laboratories in ClinVar (Variation ID 220208) and it has been identified in 0.004% (1/24956) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Teng 2004 PMID: 14714110, Yao 2009 PMID: 19324319). This nonsense variant leads to a premature termination codon at position 863, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is an established disease mechanism in LQTS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PVS1, PP1_Moderate, PM2, PS4_Supporting, PM6, PS3_supporting. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2024 | The p.R863* pathogenic mutation (also known as c.2587C>T), located in coding exon 10 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2587. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been detected in unrelated individuals with long QT syndrome (LQTS), has been shown to segregate with disease in at least one family, and has been reported to occur de novo in an affected individual (Van Langen IM et al. J Med Genet. 2003;40:141-5; Teng S et al. J Mol Med. 2004;82:189-96; Yao Y et al. Heart Rhythm. 2009;6:553-60; Zamorano-León JJ et al. J Neurogenet. 2012;26:382-6). In an assay testing KCNH2 function, this variant showed a functionally abnormal result (Teng S et al. J Mol Med. 2004;82:189-96; Yao Y et al. Heart Rhythm. 2009;6:553-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at