chr8-132174295-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004519.4(KCNQ3):c.988C>T(p.Arg330Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004519.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ3 | NM_004519.4 | c.988C>T | p.Arg330Cys | missense_variant | 6/15 | ENST00000388996.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ3 | ENST00000388996.10 | c.988C>T | p.Arg330Cys | missense_variant | 6/15 | 1 | NM_004519.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1399984Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1AN XY: 690562
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Seizures, benign familial neonatal, 2 Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | Same variant detected in 2 unrelated families - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.981, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Benign neonatal seizures Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 21417). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 18249525, 23146207). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNQ3 protein (p.Arg330Cys). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2022 | Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23146207, 16883520, 28717674, 35627257, 34474328, 18249525, 25524373, 34136434) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at