rs199472988
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000262186.10(KCNH2):c.2204C>T(p.Ser735Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S735A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000262186.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2204C>T | p.Ser735Leu | missense_variant | 9/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2204C>T | p.Ser735Leu | missense_variant | 9/15 | 1 | NM_000238.4 | ENSP00000262186 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249096Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135258
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460672Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1AN XY: 726672
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 24, 2023 | This missense variant replaces serine with leucine at codon 735 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). In vitro functional studies in HEK293 cells suggest that this variant may impact protein trafficking (PMID: 25417810), however the clinical relevance of this observation is unknown. This variant has been reported in an infant with suspected long QT syndrome (PMID: 16379539). This variant has been identified in 1/249096 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 15, 2015 | Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change may affect normal protein trafficking (PMID: 25417810), but the clinical significance of the this observation is uncertain. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant has been reported in the literature and is present in population databases (rs199472988, <0.01%). It was reported in an newborn with bradycardia, and was observed in the newborn's clinically unaffected father (PMID: 16379539). This sequence change replaces serine with leucine at codon 735 of the KCNH2 protein (p.Ser735Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2020 | Identified in a newborn with bradycardia but a normal QT interval on EKG and in the newborn's clinically unaffected father (Shim et al., 2005); Identified in conjunction with additional cardiogenetic variants in unrelated individuals referred for arrhythmia genetic testing at GeneDx, but segregation data is limited at this time; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Published functional studies in HEK293 cells demonstrate this variant may affect normal protein trafficking (Anderson et al., 2014). However, the clinical validity of these studies remains to be determined, and further functional evidence is needed to clarify the role of this variant in human disease.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67374; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16379539, 22581653, 25417810) - |
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:16379539). 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