Evidence Repository - Clinical Genome Resources

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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Variant: NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys)

CA21112664

505302 (ClinVar)

Gene: KCNQ4

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3e8e4973-8620-4a94-8c71-3bdec36a8281

HGVS expressions

NM_004700.3:c.825G>C

NM_004700.3(KCNQ4):c.825G>C (p.Trp275Cys)

NC_000001.11:g.40819463G>C

CM000663.2:g.40819463G>C

NC_000001.10:g.41285135G>C

CM000663.1:g.41285135G>C

NC_000001.9:g.41057722G>C

NG_008139.1:g.40452G>C

NG_008139.2:g.40452G>C

NM_172163.2:c.825G>C

NM_004700.4:c.825G>C

ENST00000347132.9:c.825G>C

ENST00000443478.3:n.511G>C

ENST00000506017.1:n.144G>C

ENST00000509682.6:n.825G>C

Likely Pathogenic

PP3 PM5 PM1 PM2

PP1 PP4 PM3 PM4 PM6 PVS1 BA1 BS1 BS4 BS2 BP5 BP7 BP4 BP2 BP3 PS4 PS3 PS2 PS1

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.825G>C (p.Trp275Cys) variant was found in one patient with hearing loss (PS4 not met; Partners LMM ClinVar SCV000712456.1). The p.Trp275Cys variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). A different pathogenic missense variant (p.Trp275Arg) and a likely pathogenic missense variant (p.Trp275Ser) have 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 6242, PMID: 25116015, 20301388; ClinVar Variation ID 372951). 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). Computational prediction tools and conservation analysis suggest that the p.Trp275Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant non-syndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: (PM2, PM5, PM1, PP3).

PP3

REVEL score of 0.928

PM5

NM_004700.3(KCNQ4):c.823T>C (p.Trp275Arg) is classified as Path by the ClinVar staff PMID: 25116015 (segregated with HL in 11 family members), 20301388 NM_004700.3(KCNQ4):c.824G>C (p.Trp275Ser) is classified as LP by GeneDx. Also, c.827G>C (p.Trp276Ser) variant has been reported in ClinVar as Pathogenic by the LMM, OMIM, and GeneReviews.

PM1

The variant occurs in the KCNQ4 hot spot: between amino acids 271-292.

PM2

Absent from gnomAD

PP1