Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_004700.3(KCNQ4):c.853G>A (p.Gly285Ser)

CA340532

6241 (ClinVar)

Gene: KCNQ4
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a39fbdff-7b49-469e-8890-5baad55ff075
Approved on: 2018-09-11
Published on: 2019-07-17

HGVS expressions

NM_004700.3:c.853G>A
NM_004700.3(KCNQ4):c.853G>A (p.Gly285Ser)
NC_000001.11:g.40819893G>A
CM000663.2:g.40819893G>A
NC_000001.10:g.41285565G>A
CM000663.1:g.41285565G>A
NC_000001.9:g.41058152G>A
NG_008139.1:g.40882G>A
NG_008139.2:g.40882G>A
NM_172163.2:c.853G>A
NM_004700.4:c.853G>A
ENST00000347132.9:c.853G>A
ENST00000443478.3:n.539G>A
ENST00000506017.1:n.172G>A
ENST00000509682.6:n.853G>A

Pathogenic

Met criteria codes 6
PS3_Supporting PP1_Strong PS4_Supporting PM2 PM5 PM1
Not Met criteria codes 17
BS1 BS4 BS2 BP7 BP5 PVS1 BP4 BP3 BP2 PS1 PS2 BA1 PP3 PP4 PM6 PM4 PM3

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
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.
Met criteria codes
PS3_Supporting
Functional evidence suggests the variant impacts normal function of the protein and acts in a dominant-negative manner
This study explores the heteromeric assembly of KCNQ channels in individual living cells (by expressing KCNQ subunits in Chinese hamster ovary cells). Gly285Ser variant yielded no detectable currents when expressed alone and yielded a current density 6.7% that of KCNQ4 alone when co-expressed with wild-type KCNQ4, suggesting that the Gly285Ser variant has a dominant negative effect. PubMed:18786918
First discovery of gene. The Gly285Ser variant did not yield any detectable currents when expressed in Xenopus oocytes, wheras the wild type KCNQ4 channel yielded current activation upon depolarization. When injected at 1:1 ratio with WT KCNQ4, the Gly285Ser variant reduced currents by about 90%, suggesting a strong dominant-negative effect of the variant. PubMed:10025409
PP1_Strong
Segregated with hearing loss in autosomal dominant manner in 2 and 14 affected family members in families from Kubisch 1999 and Wang 2014, respectively
Sequencing of this gene in 45 families with autosomal dominant deafness identified one French individual with Gly285Ser variant in the heterozygous state. This variant segregated with disease in two other affected members of the family PubMed:10025409
The variant was identified in a large Chinese family with postlingual, progressive hearing loss. 15 affected family members had the variant. Targeted next-gen sequencing panel of 30 ADHL-associated genes were tested. PubMed:25116015
PS4_Supporting
Seen in two affected individuals (Kubisch 1999, LMM unpublished data)
Sequencing of this gene in 45 families with autosomal dominant deafness identified one French individual with Gly285Ser variant in the heterozygous state. This variant segregated with disease in two other affected members of the family. PubMed:10025409
PM2
Variant is absent from gnomAD
PM5
p.Gly285Cys segregated with hearing loss in AD manner in 18 members of an American family (Coucke 1999)
p.Gly285Cys variant detected in American family linked to DFNA2. There were 18 affected members of the family. The linkage analysis was originally reported in Coucke 1994. PubMed:10369879
Linkage analysis (with pedigree) of American family in which p.Gly285Cys was later found in Coucke 1999 PubMed:8035838
PM1
Affects p-loop of protein, a designated mutational hot spot in KCNQ4
Not Met criteria codes
BS1
Variant is absent from gnomAD
BS4
Sequencing of this gene in 45 families with autosomal dominant deafness identified one French individual with Gly285Ser variant in the heterozygous state. This variant segregated with disease in two other affected members of the family PubMed:10025409
The variant was identified in a large Chinese family with postlingual, progressive hearing loss. 15 affected family members had the variant. Targeted next-gen sequencing panel of 30 ADHL-associated genes were tested. PubMed:25116015
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
All predictors predict a damaging effect to protein. HLWG discussed "double counting" for PP3 and PS3_supporting for this variant. Decision made to drop PP3.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
p.Gly285Cys variant detected in American family linked to DFNA2. There were 18 affected members of the family. The linkage analysis was originally reported in Coucke 1994. PubMed:10369879
Linkage analysis (with pedigree) of American family in which p.Gly285Cys was later found in Coucke 1999 PubMed:8035838
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Variant is absent from gnomAD
PP3
All predictors predict a damaging effect to protein. HLWG discussed "double counting" for PP3 and PS3_supporting for this variant. Decision made to drop PP3.
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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