rs199472751
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000155840.12(KCNQ1):c.949G>A(p.Asp317Asn) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D317Y) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000155840.12 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.949G>A | p.Asp317Asn | missense_variant | 7/16 | ENST00000155840.12 | NP_000209.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.949G>A | p.Asp317Asn | missense_variant | 7/16 | 1 | NM_000218.3 | ENSP00000155840 | P1 | |
KCNQ1 | ENST00000335475.6 | c.568G>A | p.Asp190Asn | missense_variant | 7/16 | 1 | ENSP00000334497 | |||
KCNQ1 | ENST00000496887.7 | c.688G>A | p.Asp230Asn | missense_variant | 8/16 | 5 | ENSP00000434560 | |||
KCNQ1 | ENST00000646564.2 | c.505G>A | p.Asp169Asn | missense_variant | 3/11 | ENSP00000495806 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2018 | This missense change is denoted Asp317Asn (aka D317N) at the protein level and c.949 G>A at the cDNA level. The Asp317Asn mutation (also reported as Asp222Asn and Asp188Asn due to alternative nomenclature) in KCNQ1 has been reported previously in multiple individuals with LQTS, and has been shown to co-segregate with an LQTS phenotype in at least two large families (Wollnick B et al.,1997, Saarinen K et al., 1998, Chen S et al., 2003 ). Swan et al. (1999) reported the QT prolongation is exacerbated during exercise and recovery in individuals harboring the Asp317Asn mutation, consistent with the development of symptoms during exercise for several of the patients reported (Saarinen K et al., 1998, Chen S et al., 2003, Swan H et al., 1999). Considering all publications, the Asp317Asn mutation was absent from 550 control alleles (Wollnick B et al.,1997, Saarinen K et al., 1998, Swan H et al., 1999). The Asp317Asn mutation was not identified in 400 Caucasian and African American control chromosomes tested at GeneDx, and the NHLBI ESP Exome Variant Server reports Asp317Asn was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The Asp317Asn mutation affects the pore region of the cardiac potassium voltage-gated channel, KQT-like type 1, an important functional region of the protein (Wollnick B et al.,1997). Furthermore, mutations at the same codon (Asp317Gly, Asp317Tyr) as well as in neighboring codons (Gly316Arg, Gly316Glu, Gly316Val, Lys318Asn) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s). - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 317 of the KCNQ1 protein (p.Asp317Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9302275, 9482580, 10973849, 11410559, 12702160, 23631430, 26063740). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp222Asn, p.Asp188Asn. ClinVar contains an entry for this variant (Variation ID: 53145). 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 expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9302275, 25705178). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2017 | Variant summary: The KCNQ1 c.949G>A (p.Asp317Asn) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (InterPro), and in the H5 loop, which is an important part of the pore (Wollnik_1997). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121152 control chromosomes. The variant has been reported in the literature to perfectly segregate with LQTS in at least two families (Wollnik_1997, Chen_2003), and was reported in a patient group which displayed the longest QT intervals as well as the most impaired heart rate responses to exercise compared to patient groups with other types of mutations in KCNQ1 (Swan_1999). Functional studies show the variant to abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant negative mechanism (Wollnik_1997). In addition, at-least one clinical diagnostic laboratory in ClinVar database has classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. - |
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:9302275;PMID:9482580;PMID:12702160). 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