rs864321707
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_172107.4(KCNQ2):c.917C>T(p.Ala306Val) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A306P) has been classified as Pathogenic.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.917C>T | p.Ala306Val | missense_variant | 6/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.917C>T | p.Ala306Val | missense_variant | 6/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460142Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726454
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 04, 2022 | The KCNQ2 c.917C>T (p.Ala306Val) missense variant results in the substitution of alanine at amino acid position 306 with valine. This variant has been reported in at least seven individuals with an early onset epilepsy phenotype, including in one case also associated with sudden unexpected death (PMID: 29390993; PMID: 32139178; PMID: 29455050; PMID: 32917465; PMID: 27535030; PMID: 31780880; PMID: 25959266; PMID: 26704558; PMID: 29852413; PMID: 34120799; PMID: 34055682). In four of these individuals the variant was reported to have occurred de novo (PMID: 34120799; PMID: 29852413; PMID: 27535030; PMID: 29390993). Another variant at the same amino acid position, c.916G>A p.Ala306Thr, has been reported in a heterozygous state in three probands, two with benign familial neonatal convulsions, both individuals inheriting the variant from affected parents (PMID: 9425895; PMID: 24375629). In the third proband the p.Ala306Thr variant was reported to have occurred de novo in a male child with infantile spasm, developmental delay and hypotonia but without epileptic seizures (PMID: 26138355). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.917C>T (p.Ala306Val) variant is classified as pathogenic for KCNQ2-related disorders. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2022 | This substitution is predicted to be within the transmembrane segment S6; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27535030, 23708187, 32139178, 34120799, 29390993, 26704558, 25959266, 29455050, 31780880, 34055682, 29852413) - |
Developmental and epileptic encephalopathy, 7 Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.A306V in KCNQ2 (NM_172107.4) has been reported in multiple individuals with Otahara syndrome, wherein it was proved to be de novo in some patients(Rim JH et al,Hortigüela M et al). The variant has been submitted to ClinVar as Pathogenic.The p.A306V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.A306V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 306 of KCNQ2 is conserved in all mammalian species. The nucleotide c.917 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
KCNQ2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2022 | Variant summary: KCNQ2 c.917C>T (p.Ala306Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250792 control chromosomes. c.917C>T has been reported in the literature in individuals affected with early onset epileptic encephalopathy and Ohtahara syndrome, and in multiple cases was reported as a de novo variant (Ko_2018, Kothur_2018, Fernandez-Marmiesse_2018, Sun_2021, Shellhaas_2017, Bagnall_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting codon 306 have been reported in association with Epilepsy and/or neurodevelopmental disorders in HGMD (A306P, A306T). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala306 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425895, 19453707, 26138355). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 219235). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and Ohtahara syndrome (PMID: 25959266, 26704558, 27535030, 29390993). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the KCNQ2 protein (p.Ala306Val). - |
Autosomal recessive congenital ichthyosis 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.S53W in PNPLA1 (NM_001145717.1) has been previously reported in homozygous state in an affected patient. The patient had a collodion membrane at birth (Boyden LM et al).The variant has been submitted to ClinVar as Pathogenic based on the same. The p.S53W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between serine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Likely Pathogenic. - |
Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at