NM_004700.4(KCNQ4):c.785A>T (p.Asp262Val) AND Autosomal dominant nonsyndromic hearing loss 2A

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000655887.2

Allele description [Variation Report for NM_004700.4(KCNQ4):c.785A>T (p.Asp262Val)]

NM_004700.4(KCNQ4):c.785A>T (p.Asp262Val)

Gene:

KCNQ4:potassium voltage-gated channel subfamily Q member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_004700.4(KCNQ4):c.785A>T (p.Asp262Val)

HGVS:

NC_000001.11:g.40819423A>T
NG_008139.3:g.40637A>T
NM_004700.3:c.785A>T
NM_004700.4:c.785A>TMANE SELECT
NM_172163.3:c.785A>T
NP_004691.2:p.Asp262Val
NP_751895.1:p.Asp262Val
LRG_1378t1:c.785A>T
LRG_1378:g.40637A>T
LRG_1378p1:p.Asp262Val
NC_000001.10:g.41285095A>T
NG_008139.1:g.40412A>T
NG_008139.2:g.40412A>T
NM_004700.2:c.785A>T

Protein change:

D262V

Links:

dbSNP: rs80358275

NCBI 1000 Genomes Browser:

rs80358275

Molecular consequence:

NM_004700.4:c.785A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172163.3:c.785A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 2A
Synonyms:: DFNA 2 Nonsyndromic Hearing Loss; Deafness, autosomal dominant 2A; Autosomal dominant nonsyndromic deafness 2A
Identifiers:: MONDO: MONDO:0010817; MedGen: C2677637; Orphanet: 90635; OMIM: 600101

Recent activity

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Homo sapiens keratin associated protein 3.3 (KAP3.3), mRNA
Homo sapiens keratin associated protein 3.3 (KAP3.3), mRNA
gi|15055510|ref|NM_033185.1|

Nucleotide
PQA68_gp13 [Yersinia phage vB_YenM_06.16-2]
PQA68_gp13 [Yersinia phage vB_YenM_06.16-2]
Gene ID:77940374

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000777816	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no assertion criteria provided	Pathogenic (Aug 20, 2015)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 26036578, 20301388
SCV005086685	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18941426, 31995783, 32382995, 34622280, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000777816

ClinVar Staff, National Center for Biotechnology Information (NCBI)

no assertion criteria provided

Pathogenic
(Aug 20, 2015)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV005086685

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 21, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Description

This variant used to be reported in GeneReviews NBK1209.: SCV000777816

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

Wasano K, Mutai H, Obuchi C, Masuda S, Matsunaga T.

Biochem Biophys Res Commun. 2015 Aug 7;463(4):582-6. doi: 10.1016/j.bbrc.2015.05.099. Epub 2015 May 31.

PubMed [citation]

PMID:: 26036578

DFNA2 Nonsyndromic Hearing Loss.

Smith RJH, Hildebrand M.

2008 Apr 4 [updated 2018 May 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301388

See all PubMed Citations (7)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000777816.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086685.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with autosomal dominant deafness 2A (MIM#600101). The exact mechanism exerted by premature termination codons remains unknown. Dominant negative is unlikely, as these mutant proteins lack the C-terminal necessary for heteromultimer formation (PMID: 34622280). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a region where missense variants cluster within the C-terminal end of the ion transport domain (DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change, p.(Asp262Gly), has been previously classified as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in an individual with autosomal dominant nonsyndromic hearing loss but has been reported both without classification and as a VUS (PMIDs: 18941426, 32382995). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. CHO cells co-transfected with WT and p.(Asp262Val) had no measurable outward current compared to WT cells, indicating that the variant induced channel deficiency (PMID: 31995783). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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