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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_004086.2(COCH):c.355G>A (p.Ala119Thr)

CA253893

6613 (ClinVar)

Gene: COCH
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cb0a2192-d76a-4556-a2d3-b0f2d2569f1e
Approved on: 2025-08-26
Published on: 2025-09-23

HGVS expressions

NM_004086.2:c.355G>A
NM_004086.2(COCH):c.355G>A (p.Ala119Thr)
NC_000014.9:g.30878926G>A
CM000676.2:g.30878926G>A
NC_000014.8:g.31348132G>A
CM000676.1:g.31348132G>A
NC_000014.7:g.30417883G>A
NG_008211.2:g.9392G>A
ENST00000216361.9:c.550G>A
ENST00000396618.9:c.355G>A
ENST00000555117.2:c.355G>A
ENST00000643575.1:c.355G>A
ENST00000643697.1:n.600G>A
ENST00000644874.2:c.355G>A
ENST00000216361.8:c.355G>A
ENST00000396618.7:c.355G>A
ENST00000460581.6:c.19G>A
ENST00000475087.5:c.355G>A
ENST00000553772.5:c.239+1198G>A
ENST00000553833.5:n.509G>A
ENST00000555881.5:c.83-1526G>A
ENST00000556908.5:c.307G>A
ENST00000557065.1:c.156-497G>A
NM_001135058.1:c.355G>A
NR_038356.1:n.1618-2374C>T
NM_001347720.1:c.550G>A
NM_004086.3:c.355G>A
NM_001135058.2:c.355G>A
NM_001347720.2:c.550G>A
More

Uncertain Significance

Met criteria codes 1
BS3_Supporting
Not Met criteria codes 25
BP2 BP3 BP1 BP4 BP5 BP7 PS3 PS2 PS4 PS1 PP4 PP1 PP2 PP3 PM6 PM2 PVS1 PM3 PM1 PM5 PM4 BA1 BS2 BS4 BS1

Evidence Links 2

Expert Panel

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.355G>A (NM_004086.3) variant in COCH gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 119 p.(Ala119Thr). The highest population minor allele frequency in gnomAD v.4 is 0.08199% (7/44876 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational Revel gives a score of 0.394, which is neither above nor below the thresholds predicting a damaging or benign impact on COCH function. Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion (PMID: 25230692) (BS3_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMPcriteria applied, as specified by the ClinGen ClinGen Hearing Loss VCEP: (BS3_Supporting) (Hearing Loss VCEP specifications version 2; 8/26/2025)
Met criteria codes
BS3_Supporting
Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion. While this not supporting evidence for pathogenicity, other mechanisms of pathogenicity cannot be ruled out.
Wild-type cochlin was localized in the ER and compacted in the Golgi complex. Coch protein containing the p.A119T variant was also found to localize in the ER and Golgi complex. Secretion studies showed that the p.A119T mutated protein was detected in the media similarly to wild-type cochlin. PubMed:25230692
Not Met criteria codes
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL score does not meet the criteria for BP4 or PP3.
BP5
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
PS3
Functional studies show no differences between wild-type and p.A119T variant cochlin localization and secretion. While this not supporting evidence for pathogenicity, other mechanisms of pathogenicity cannot be ruled out.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Not enough probands to meet PS4_Supporting.
23 Japanese probands with autosomal dominant hearing loss were screened for COCH variants. The p.A119T variant was observed in one individual with a personal and family history suggestive of autosomal dominantly inherited hearing loss and vestibular dysfunction. The variant was not observed in 4 unaffected family members. Edited by Alex C (3/30/2018). PubMed:14512963
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL score does not meet the criteria for BP4 or PP3.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v.4 is 0.08199% (7/44876 alleles) in the East Asian population
PVS1
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
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
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
BA1
The highest population minor allele frequency in gnomAD v.4 is 0.08199% (7/44876 alleles) in the East Asian population Found in one individual (0.045) in HGVD (Japanese general population).
BS2
Found in one individual (0.045) in HGVD (Japanese general population). But COCH is associated with adult-onset HL, and thus this observation is likely irrelevant.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The highest population minor allele frequency in gnomAD v.4 is 0.08199% (7/44876 alleles) in the East Asian population Found in one individual (0.045) in HGVD (Japanese general population).
Curation History
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