rs199473014
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000238.4(KCNH2):c.2887C>A(p.Pro963Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000206 in 1,601,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2887C>A | p.Pro963Thr | missense_variant | Exon 12 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2887C>A | p.Pro963Thr | missense_variant | Exon 12 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1867C>A | p.Pro623Thr | missense_variant | Exon 8 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3720C>A | non_coding_transcript_exon_variant | Exon 10 of 13 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000207 AC: 30AN: 1448824Hom.: 0 Cov.: 36 AF XY: 0.0000236 AC XY: 17AN XY: 719732
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:2
This missense variant replaces proline with threonine at codon 963 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has no detectable impact on membrane surface expression or biophysical gating properties (PMID: 29331839, 31493592). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19841300, 22949429, 28861002). This variant has also been reported in two related individuals affected with recurrent sudden infant death syndrome and in two other family members who had no cardiac phenotypes (PMID: 29331839). This variant has not been identified 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. -
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 963 of the KCNH2 protein (p.Pro963Thr). 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 individual(s) with long QT syndrome and/or sudden infant death syndrome (PMID: 19841300, 29331839). ClinVar contains an entry for this variant (Variation ID: 67449). 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 does not substantially affect KCNH2 function (PMID: 29331839, 31493592). 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. -
not provided Uncertain:1
The p.Pro963Thr variant (rs199473014) was reported in one patient in a cohort of ~400, and determined as one of C-terminal variants in KCNH2 with elevated allele frequency in Long-QT cases compared to controls (Kapa, 2009). Further analysis using a combination of prediction tools concluded this variant might be benign (Giudicessi, 2012). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0009 percent (identified on 2 out of 214,534 chromosomes). It is also reported in ClinVar (Variation ID: 67449) without any clinical significance. The proline at position 963 is moderately conserved and computational analyses of the effects of the p.Pro963Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro963Thr variant with certainty. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
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Cardiac arrhythmia Uncertain:1
This missense variant replaces proline with threonine at codon 963 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has no detectable impact on membrane surface expression or biophysical gating properties (PMID: 29331839, 31493592). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 19841300, 22949429, 28861002). This variant has also been reported in two related individuals affected with recurrent sudden infant death syndrome and in two other family members who had no cardiac phenotypes (PMID: 29331839). This variant has not been identified 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. -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19841300). 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