1-40819465-G-T

Variant names:

• chr1-40819465-G-T
• rs80358277
• NM_004700.4:c.827G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004700.4(KCNQ4):​c.827G>T​(p.Trp276Leu) 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. 13/22 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. W276R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNQ4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_004700.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40819464-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1699203.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 1-40819465-G-T is Pathogenic according to our data. Variant chr1-40819465-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2632379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.827G>T	p.Trp276Leu	missense	Exon 5 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.827G>T	p.Trp276Leu	missense	Exon 5 of 13	NP_751895.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.827G>T	p.Trp276Leu	missense	Exon 5 of 14	ENSP00000262916.6
	KCNQ4	ENST00000509682.6	TSL:5	c.827G>T	p.Trp276Leu	missense	Exon 5 of 13	ENSP00000423756.2
	KCNQ4	ENST00000443478.3	TSL:5	c.512G>T	p.Trp171Leu	missense	Exon 4 of 13	ENSP00000406735.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 18, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 23717403, 27068579)

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 276 of the KCNQ4 protein (p.Trp276Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 27068579; Invitae). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Trp276 amino acid residue in KCNQ4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12112653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

KCNQ4-related disorder Pathogenic:1

May 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ4 c.827G>T variant is predicted to result in the amino acid substitution p.Trp276Leu. This variant was reported in an individual with autosomal dominant hearing loss (Table S1, Sommen et al. 2016. PubMed ID: 27068579). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Trp276Ser) has been reported to be causative for autosomal dominant hearing loss (Coucke et al. 1999. PubMed ID: 10369879; Table S4, Moteki et al. 2015. PubMed ID: 26346818). Taken together, the c.827G>T (p.Trp276Leu) variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.85		Gain of helix (P = 0.0496)
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80358277; hg19: chr1-41285137;