chr7-150974830-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000238.4(KCNH2):c.188C>A(p.Pro63His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,246 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P63L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.188C>A | p.Pro63His | missense_variant | 2/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.188C>A | p.Pro63His | missense_variant | 2/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.411C>A | non_coding_transcript_exon_variant | 2/9 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000424 AC: 1AN: 235826Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128904
GnomAD4 exome Cov.: 34
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | Reported in association with LQTS (Lieve et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 22396785) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 22, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2016 | Variant summary: The KCNH2 c.188C>A variant is a missense change that alters a conserved nucleotide, resulting in an amino acid change from a non-polar Pro to a positively charged His residue. 4/4 in silico tools predict deleterious outcome (SNPs&GO not captured due to low reliability index). However, at the time of classification, functional studies had not been carried out to confirm these in silico predictions. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0013% (1/79290 chromosomes tested), which does not exceed the maximal expected allele frequency for a pathogenic KCNH2 variant. Additionally, the variant of interest has been reported in at least 1 patient with LQTS from the literature and was classified by a clinical diagnostic center as Pathogenic. Furthermore, multiple nearby missense mutations, such as c.182A>G (p.Q61R), c.185G>A (p.R62Q), c.191G>A (p.C64Y), andc.192C>G (p.C64W), have been reported in association with LQTS, further supporting the functional importance of this region. However, additional clinical information and segregation data are needed to evaluate the clinical significance of this missense change with confidence. Taken together, the variant was classified as a VUS until more information becomes available. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2022 | The p.P63H variant (also known as c.188C>A), located in coding exon 2 of the KCNH2 gene, results from a C to A substitution at nucleotide position 188. The proline at codon 63 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in multiple individuals with a diagnosis of long QT syndrome (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Invitae pers. comm.; GeneDx pers. comm.; Ambry internal data). Additionally, this alteration has been predicted to be disruptive to the PAS domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 63 of the KCNH2 protein (p.Pro63His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 23631430; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200559). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at