chr11-2847848-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000218.3(KCNQ1):c.1876G>A(p.Gly626Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,571,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000111 AC: 2AN: 179998Hom.: 0 AF XY: 0.0000103 AC XY: 1AN XY: 96966
GnomAD4 exome AF: 0.0000282 AC: 40AN: 1418906Hom.: 0 Cov.: 31 AF XY: 0.0000328 AC XY: 23AN XY: 701828
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:3
Identified in association with LQTS and sudden infant death syndrome (SIDS) (PMID: 15840476, 19716085, 16922724, 19322600); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21215473, 23304551, 34930020, 15840476, 16922724, 19716085, 28316956, 19322600, 31019283, 31043699) -
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The p.Gly626Ser variant in KCNQ1 has been reported in 1 individual with long QT syndrome (Tester 2005 PMID: 15840476) and in case of infant sudden death, but was also present the asymptomatic mother (Millat 2006 PMID: 16922724). It has also been identified in 0.004% (1/24468) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4. -
Long QT syndrome 1 Pathogenic:1Uncertain:1
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Long QT syndrome Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 626 of the KCNQ1 protein (p.Gly626Ser). 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 clinical features of KCNQ1-related conditions (PMID: 15840476, 19322600). ClinVar contains an entry for this variant (Variation ID: 53022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ1 protein function. 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. -
Cardiovascular phenotype Uncertain:1
The c.1876G>A (p.G626S) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1876, causing the glycine (G) at amino acid position 626 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cardiac arrhythmia Uncertain:1
This missense variant replaces glycine with serine at codon 626 of the KCNQ1 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). A functional study has shown that this variant has no significant impact on channel peak current density (PMID: 34930020). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 16922724), in an individual suspected of having long QT syndrome (PMID: 15840476), and in a few unaffected individuals (PMID: 19322600, 34930020). This variant has been identified in 2/179998 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. -
Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:16922724;PMID:19716085). 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