1-40819893-G-A

Position:

• chr1-40819893-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4_Supporting PP1_Strong PM1 PM5 PS3_Supporting PM2

This summary comes from the ClinGen Evidence Repository: The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID:10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID:10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID:23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID:10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340532/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.853G>A	p.Gly285Ser	missense_variant	6/14	ENST00000347132.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.853G>A	p.Gly285Ser	missense_variant	6/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.853G>A	p.Gly285Ser	missense_variant	6/13	5		A1
KCNQ4	ENST00000443478.3	c.541G>A	p.Gly181Ser	missense_variant	5/13	5
KCNQ4	ENST00000506017.1	n.172G>A		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 2A Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2011	- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 11, 2018

The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID: 10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly285 amino acid residue in KCNQ4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8035838, 10369879, 20832469, 20966080, 23717403). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 10025409, 20966080, 23750663). 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. ClinVar contains an entry for this variant (Variation ID: 6241). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10025409, 25116015). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the KCNQ4 protein (p.Gly285Ser). -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2018

The p.Gly285Ser variant in KCNQ4 has been reported in at least three individuals with hearing loss, and segregated with disease in over 15 affected relatives fr om two families (LMM unpublished data, Kubisch 1999, Wang 2014). It was absent f rom large population studies. In vitro functional studies support an impact on p rotein function and suggest that the variant may act in a dominant-negative mann er (Kubisch 1999, Bal 2008). Furthermore, the p.Gly285Ser variant falls within t he highly conserved pore-forming region of KCNQ4 (Oza 2018). Supporting the into lerance of this position to variation, a different amino acid change at the same position (p.Gly285Cys) has been reported in one family with hearing loss (Couck e 1999). Finally, this variant was classified as Pathogenic on 9/11/2018 by the ClinGen-approved Hearing Loss Expert Panel (Variation ID 6241). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant no nsyndromic hearing loss. ACMG/AMP criteria applied: PP1_Strong, PM1, PM2, PP3, P S3_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.7	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.020	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.97, 0.89
MutPred		0.94		Gain of glycosylation at G285 (P = 0.0172);Gain of glycosylation at G285 (P = 0.0172);Gain of glycosylation at G285 (P = 0.0172);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937588; hg19: chr1-41285565; COSMIC: COSV61273409;