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]

Variant: NM_004086.2(COCH):c.263G>A (p.Gly88Glu)

CA253885

6609 (ClinVar)

Gene: COCH (HGNC:1690)

Condition: nonsyndromic genetic deafness (MONDO:0019497)

Inheritance Mode: Autosomal dominant inheritance

UUID: 22c58c35-f743-4a68-82cd-2c83be83263f

Approved on: 2026-09-16

Published on: 2026-09-30

HGVS expressions

NM_004086.2(COCH):c.263G>A (p.Gly88Glu)

NM_004086.2:c.263G>A

NC_000014.9:g.30878834G>A

CM000676.2:g.30878834G>A

NC_000014.8:g.31348040G>A

CM000676.1:g.31348040G>A

NC_000014.7:g.30417791G>A

NG_008211.2:g.9300G>A

ENST00000216361.9:c.458G>A

ENST00000396618.9:c.263G>A

ENST00000555117.2:c.263G>A

ENST00000643575.1:c.263G>A

ENST00000643697.1:n.508G>A

ENST00000644874.2:c.263G>A

ENST00000216361.8:c.263G>A

ENST00000396618.7:c.263G>A

ENST00000460581.6:c.-74G>A

ENST00000475087.5:c.263G>A

ENST00000553772.5:c.239+1106G>A

ENST00000553833.5:n.417G>A

ENST00000555881.5:c.83-1618G>A

ENST00000556908.5:c.215G>A

ENST00000557065.1:c.156-589G>A

NM_001135058.1:c.263G>A

NR_038356.1:n.1618-2282C>T

NM_001347720.1:c.458G>A

NM_004086.3:c.263G>A

NM_001135058.2:c.263G>A

NM_001347720.2:c.458G>A

Pathogenic

PP1_Strong PS4_Supporting PP3 PS3 PM2_Supporting

Evidence Links 9

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2.0

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The NM_004086.3:c.263G>A variant in COCH is a missense variant predicted to cause substitution of Glycine to Glutamic acid at amino acid 88 (p.Gly88Glu). The highest population minor allele frequency in gnomAD v4.1.1 is 0.0006780% (8/1180018 alleles -European [non-Finnish], PM2_Supporting met). The computational predictor REVEL yields a score of 0.933 (PP3 met). The variant has been reported to segregate with progressive, late-onset HL and concomitant vestibular dysfunction in 16 affected family members from 4 families. (PP1_Strong, PS4_Supporting met; PMID: 9806553, 16151339, 25780252, 42195045). Vestibular-evoked potential, distortion product otoacoustic emission and auditory brainstem response measurements as well as histopathology in a knock-in mouse model showed dysfunctional vestibular function, progressive hearing loss, and middle ear granulocytic aggregation. Additionally, immunohistochemical staining showed that G88E protein expression inhibits co-localization with the extracellular matrix of HeLa cells while cell death analysis showed an increase in cytotoxicity in primary fibrocytes. Immunoprecipitation experiments indicated that G88E protein dimerizes with wild-type cochlin and forms agent-resistant oligomers. This was further confirmed by experiments in HEK293 cells showing reduced susceptibility of G88E-containing cochlin to aggrecanase cleavage. Overall, these studies indicate that this variant impacts protein function (PS3 met; PMID: 12843317, 12928864, 18697796, 20228067, 21073934, 25049087, 26256111, 35901072). In summary, based on the current evidence (PP1_Strong, PS3, PM2_Supporting, PP3 & PS4_Supporting), the variant NM_004086.3(COCH):c.263G>A(Gly88Glu) is classified as pathogenic for autosomal dominant non-syndromic SNHL based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 9/16/2026).

PP1_Strong

The variant has been reported to segregate with progressive, late-onset HL and concomitant vestibular dysfunction in 16 affected family members from 4 families. (PMID: 9806553, 16151339, 25780252, 42195045)

PS4_Supporting

The variant has been reported in four probands with progressive, late-onset HL and concomitant vestibular dysfunction (PMID: 9806553, 16151339, 25780252, 42195045)

PP3

The computational predictor REVEL yields a score of 0.933.

PS3

Vestibular-evoked potential, distortion product otoacoustic emission and auditory brainstem response measurements as well as histopathology in a knock-in mouse model showed dysfunctional vestibular function, progressive hearing loss, and middle ear granulocytic aggregation. Additionally, immunohistochemical staining showed that G88E protein expression inhibits co-localization with the extracellular matrix of HeLa cells while cell death analysis showed an increase in cytotoxicity in primary fibrocytes. Immunoprecipitation experiments indicated that G88E protein dimerizes with wild-type cochlin and forms agent-resistant oligomers. This was further confirmed by experiments in HEK293 cells showing reduced susceptibility of G88E-containing cochlin to aggrecanase cleavage. Overall, these studies indicate that this variant impacts protein function

see above PubMed:25049087

see above PubMed:12928864

see above PubMed:26256111

see above PubMed:12843317

see above PubMed:21073934

see above PubMed:18697796

see above PubMed:34735822

see above PubMed:20228067

see above PubMed:35901072

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.1 is 0.0006780% (8/1180018 alleles -European [non-Finnish]).

Curation History

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