rs199473398
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_000218.3(KCNQ1):c.556G>A(p.Gly186Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G186R) has been classified as Pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.556G>A | p.Gly186Ser | missense_variant | Exon 3 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.175G>A | p.Gly59Ser | missense_variant | Exon 3 of 16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.295G>A | p.Gly99Ser | missense_variant | Exon 4 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.478-12729G>A | intron_variant | Intron 2 of 10 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:1
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KCNQ1-related disorder (PMID: 17470695). Different missense changes at the same codon (p.Gly186Arg, p.Gly186Asp, p.Gly186Cys, p.Gly186Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053065, VCV000200894, VCV000207967, VCV000432149). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Long QT syndrome Pathogenic:1
The c.556G>A (p.Gly186Ser) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in heterozygous status in at least ten individuals with Long QT syndrome 1 (LQTS1) (PMID: 17470695, 14678125). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.937). This variant is found to be absent in the general population database (gnomAD). Different missense changes at the same codon (p.Gly186Arg, p.Gly186Asp, p.Gly186Cys, p.Gly186Val) have been reported as pathogenic/ likely pathogenic by several ClinVar submitters (ClinVar ID: 53065, 207967, 200894, 432149). Therefore, the c.556G>A (p.Gly186Ser) variant in the KCNQ1 gene is classified as likely pathogenic. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14678125;PMID:17470695;PMID:19862833). 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