rs80358278
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_004700.4(KCNQ4):āc.842T>Cā(p.Leu281Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,268 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 Pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L281L) has been classified as Benign.
Frequency
Consequence
NM_004700.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ4 | NM_004700.4 | c.842T>C | p.Leu281Ser | missense_variant | 6/14 | ENST00000347132.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ4 | ENST00000347132.10 | c.842T>C | p.Leu281Ser | missense_variant | 6/14 | 1 | NM_004700.4 | P2 | |
KCNQ4 | ENST00000509682.6 | c.842T>C | p.Leu281Ser | missense_variant | 6/13 | 5 | A1 | ||
KCNQ4 | ENST00000443478.3 | c.530T>C | p.Leu177Ser | missense_variant | 5/13 | 5 | |||
KCNQ4 | ENST00000506017.1 | n.161T>C | non_coding_transcript_exon_variant | 3/11 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461268Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726996
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Aug 20, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 14, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 05, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | ClinVar contains an entry for this variant (Variation ID: 6246). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10571947). 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 leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the KCNQ4 protein (p.Leu281Ser). 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 KCNQ4 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 23750663). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2020 | Published functional studies demonstrate the L281S mutation leads to non-functional channels and improper trafficking of mutant channels to the cell surface with a dominant negative effect on WT channels (Kim et al., 2011; Gao et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10571947, 23776385, 18797286, 12408061, 26036578, 24616153, 11252765, 28802383, 25116015, 23399560, 21951272, 17033161, 23750663, 20966080, 22785243) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at