7-150951511-C-T
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.1882G>A(p.Gly628Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G628V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
Publications
- long QT syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- long QT syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- short QT syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- short QT syndrome type 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- Brugada syndromeInheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
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ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KCNH2 | NM_000238.4 | c.1882G>A | p.Gly628Ser | missense_variant | Exon 7 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNH2 | ENST00000262186.10 | c.1882G>A | p.Gly628Ser | missense_variant | Exon 7 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461872Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727238 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:5
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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, PMID: 10753933; PMID: 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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional ion transport domain, within the pore (UniProt). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. There are multiple alternative changes at the same amino acid position reported in ClinVar. At least one alternative change to an alanine has been reported in individual with LQT (ClinVar, PMID: 19996378). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported pathogenic variant associated with LQT (ClinVar, PMID: 10973849, 16922724, 19996378, 22949429, 25608792, 27492745). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
The KCNH2 c.1882G>A (p.Gly628Ser) variant is a missense variant that has been reported in at least five studies and is found in a total of six individuals with long QT syndrome, including at least two neonates, all in a heterozygous state (Curran et al. 1995; Splawski et al. 2000; Lupoglazoff et al. 2004; Shim et al. 2005; Kapa et al. 2009). The variant was confirmed to be de novo in two of the cases and was not identified in the parents of a third, but parentage was not confirmed. The p.Gly628Ser variant was absent from more than 1600 controls and it is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. The variant is found in the pore-forming domain of the protein and variants in this region are known to affect potassium ion transport (Curran et al. 1995; Shim et al. 2005). Based on the collective evidence and the application of the ACMG criteria, the p.Gly628Ser variant is classified as pathogenic for long QT syndrome.
not provided Pathogenic:3
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Gly628Ser Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least 6 unrelated cases of Long QT. There is no segregation data available. Curran et al (1995) was the first to report this variant in a proband with Long QT suggesting the connection between LongQt and KCNH2 (then known as the HERG gene). It was a de novo mutation. No clinical data or segregation data was given. Splawski et al. (2000) reported this variant in two families with LQT from a cohort of 262 individuals with LQTS. The authors tested for mutations in all known arrhythmia genes. No specific phenotype data was given for the patients. Lupoglazoff et al (2004) reported this variant in a neonate with fetal bradycardia and heart failure. This was a de novo mutation. No segregation data was given. Shim et al. 2005 reported this variant in a neonate with congenital LQT and a double heterozygote for a novel SCN5A varaint-V1950L. The patient was implanted with an ICD at 3 days. The patient's mother had LQT and the SCN5A mutation. The father did not carry the KCNH2 variant and it was thus de novo and thought to contribute to the patient's phenotype. Kapa et al., 2009 (Ackerman) reported this variant in one individual from their cohort of 388 LQT syndrome patients from 1997 to 2007. All had a clinical diagnostic score (Schwartz score) of >4 or a corrected QT interval (QTc) >480 ms. They did mutation analysis for KCNQ1, KCNH2, and SCN5A. Specific case data was not given for the patient with this variant. They reported an extremely high probability (EPV100%; 95% CI, 95 to 100) of pathogenicity for missense mutations localizing to the linker, transmembrane, and pore regions of KCNH2 but lower EPVs for missense mutations in the N terminus (63%; 95% CI, 17 to 84) or C terminus of KCNH2. This variant occurs in the pore-forming domain, which is highly conserved in all potassium channel subunits (Curran et al. 1995). This substitution in vitro caused potassium ion selectivity loss. This substitution has also been found to correctly insert into the cell surface membrane, but does not generate Kv11.1 channel function, presumable because of its location within the potassium selectivity filter (Anderson et al. 2006). This variant results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine, at a position that is highly conserved. Other variants have been reported in association with disease at this codon (Gly628Ala, Gly628Val) and nearby codons (Phe627Leu, Phe627Ile, Asn629Asp, Asn629Ser, Asn629Thr, Asn629Ile, Asn629Lys). In total the variant has not been seen in ~8,100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 628 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/22/13). The variant was not observed in the following published control samples: Kapa did not report this variant in >1300 control individuals, Lupoglazoff did not report this variant in 100 control individuals, Splawski did not report this variant in 200 control individuals.
The G628S pathogenic variant in the KCNH2 gene has been reported multiple times in association with LQTS, and was not seen in >1,369 healthy control individuals (Curran et al., 1995; Splawski et al., 2000; Shim et al., 2005; Anderson et al., 2006; Kapa et al., 2009; Giudicessi et al., 2012). Of note, G628S was identified as a de novo variant in a neonate presenting with fetal bradycardia, torsades de pointes, 2:1 atrioventricular block, a QTc of 544 ms, and heart failure; family history was negative and both parents had a normal QTc interval (Lupoglazoff et al., 2004). Furthermore, the G628S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G628S variant results in a non-conservative amino acid substitution of a non-polar Glycine residue with a polar Serine residue, at a position that is highly conserved and important for potassium ion selectivity (Curran et al., 1995). The G628S variant is located in the pore-forming domain of the protein and alters the selectivity filter motif (Curran et al., 1995). Multiple functional studies demonstrated that G628S results in a loss of potassium channel function (Anderson et al., 2006; Brunner et al., 2008; Ren et al., 2010). In summary, G628S in the KCNH2 gene is interpreted as a pathogenic variant.
Short QT syndrome type 1 Pathogenic:1
Long QT syndrome Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 628 of the KCNH2 protein (p.Gly628Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 7889573, 14998624, 16922724, 17088455, 22949429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14427). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 8700910, 9694858, 23303164). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular phenotype Pathogenic:1
The p.G628S pathogenic mutation (also known as c.1882G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1882. The glycine at codon 628 is replaced by serine, an amino acid with similar properties. This alteration impacts the highly conserved ion selectivity filter (SVGFGN) located between transmembrane helices S5 and S6. This variant has been identified in numerous patients with long QT syndrome (LQTS) and was reported to be de novo in several of them (e.g., Curran ME et al. Cell. 1995;80:795-803; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004;43:826-30; Millat G et al. Clin. Genet. 2006;70:214-27; Horigome H et al. Circ Arrhythm Electrophysiol, 2010;3:10-7; Crimmins S et al. J Clin Ultrasound. 2017;45:168-170). Multiple functional studies, including a mammalian model, suggest G628S leads to a loss of potassium selectivity, reduced channel function, and prolonged QT (Zhou Z et al. J. Biol. Chem. 1998;273:21061-6; Brunner M et al. J. Clin. Invest. 2008;118:2246-59; Es-Salah-Lamoureux Z et al. Biophys. J. 2011;101:662-70; Jou CJ et al. Circ. Res. 2013;112:826-30). In addition, internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
KCNH2-related disorder Pathogenic:1
The KCNH2 c.1882G>A variant is predicted to result in the amino acid substitution p.Gly628Ser. This variant was reported in numerous individuals with long QT syndrome, including at least two cases confirmed to have occurred de novo (Curran et al. 1995. PubMed ID: 7889573; Splawski et al. 2000. PubMed ID: 10973849; Lupoglazoff et al. 2004. PubMed ID: 14998624; Shim et al. 2005. PubMed ID: 16379539; Table S2, Giudicessi et al. 2012. PubMed ID: 22949429; Supplementary table, Marschall et al. 2019. PubMed ID: 31737537). Functional studies showed that this variant disrupts channel permeation and repolarization (Anderson et al. 2006. PubMed ID: 16432067; Brunner et al. 2008. PubMed ID: 18464931; Es-Salah-Lamoureux et al. 2011. PubMed ID: 21806934; Table SII, Jou et al. 2013. PubMed ID: 23303164). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:7889573;PMID:10973849;PMID:11854117;PMID:14998624;PMID:15840476;PMID:16379539;PMID:16432067;PMID:16922724;PMID:18441445;PMID:18464931;PMID:19716085;PMID:19841300;PMID:20833965;PMID:21806934;PMID:9694858;PMID:22876326). 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