7-150974775-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The ENST00000262186.10(KCNH2):āc.243G>Cā(p.Gln81His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,142 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q81E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000262186.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.243G>C | p.Gln81His | missense_variant | 2/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.243G>C | p.Gln81His | missense_variant | 2/15 | 1 | NM_000238.4 | ENSP00000262186 | P1 | |
KCNH2 | ENST00000532957.5 | n.466G>C | non_coding_transcript_exon_variant | 2/9 | 2 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1454142Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 722974
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Long QT syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMIDs: 10753933, 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PAS 9 domain (DECIPHER). (I) 0704 - Other missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. p.(Gln81Pro) and p.(Gln81Arg) have been reported in individuals with a diagnosis of LQTS and suspected LQTS, respectively (PMIDs: 34546463, 27041096). In addition, p.(Gln81Lys) has been reported as a VUS in an individual with epilepsy (PMID: 31696929). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as a VUS by two clinical testing laboratories, including in an individual with LQTS, three individuals with possible LQTS and one unaffected individual (ClinVar, personal communication). It has also been reported in a child who died in her sleep at 21 months old who had a clinical history of febrile convulsions, and in her asymptomatic father (PMID: 20167303). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub | Sep 08, 2017 | This variant has not been detected in control populations (ExAC), and has been reported once in the literature, in a 21 month old who died suddenly, it was also detected in the healthy father (Gladding et al 2010 Heart Rhythm 7(4):481-6) . The variant is located in the N-terminus region, which is a hotspot for mutations. The affecte amino acid is highly conserved, how in silico tools offer conflicting evidence as to the damaging effect on protein function - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2022 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67399). This missense change has been observed in individual(s) with sudden death after a history of febrile convulsions (PMID: 20167303). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 81 of the KCNH2 protein (p.Gln81His). - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20167303). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at