rs878854350
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.1686-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000218.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1686-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 15 | 1 | NM_000218.3 | ENSP00000155840.2 | |||
KCNQ1 | ENST00000335475.6 | c.1305-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 15 | 1 | ENSP00000334497.5 | ||||
KCNQ1 | ENST00000496887.7 | c.1329-2A>G | splice_acceptor_variant, intron_variant | Intron 13 of 15 | 5 | ENSP00000434560.2 | ||||
KCNQ1 | ENST00000646564.2 | c.1146-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 10 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461768Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727186
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:2
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not provided Pathogenic:2
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Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the compound heterozygous state with another KCNQ1 variant in an individual with long QT syndrome (Vyas et al., 2016a; Vyas et al., 2016b); This variant is associated with the following publications: (PMID: 34319147, 27485560, 27041150) -
Long QT syndrome Pathogenic:2
Variant summary: KCNQ1 c.1686-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251050 control chromosomes (gnomAD). c.1686-2A>G has been reported in the literature in individuals affected with Autosomal Recessive RomanoWard Syndrome or Long QT Syndrome (Vyas_2016, Choi_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27041150, 34319147). ClinVar contains an entry for this variant (Variation ID: 207973). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This sequence change affects an acceptor splice site in intron 13 of the KCNQ1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in a individual affected with a recessive form of long QT syndrome (PMID: 27041150). ClinVar contains an entry for this variant (Variation ID: 207973). Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in KCNQ1 are known to be pathogenic (PMID: 19862833). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.1686-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 14 in the KCNQ1 gene. This variant was reported in an individual with Romano-Ward syndrome, who was a compound heterozygote with an additional KCNQ1 alteration (p.R533W, c.1597C>T); the proband's father had a QTc of 415ms and was reported to be heterozygous for the c.1686-2A>G variant (Vyas B et al. Am. J. Med. Genet. A, 2016 Jun;170:1510-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at