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]

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: 2022-06-15
Published on: 2023-02-06

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:n.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
NM_004086.3(COCH):c.355G>A (p.Ala119Thr)
More

Uncertain Significance

Met criteria codes 2
BS3_Supporting PM2_Supporting
Not Met criteria codes 24
PM3 PM1 PM5 PM4 PS3 PS2 PS4 PS1 BA1 PM6 PP4 PP1 PP2 PP3 PVS1 BS4 BS1 BS2 BP5 BP7 BP2 BP3 BP1 BP4

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.355G>A variant in COCH is a missense variant predicted to cause substitution of alanine by threonine at amino acid 119. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor 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 (BS3_Supporting). While this is not supporting evidence for pathogenicity, other mechanisms of pathogenicity cannot be ruled out. Due to conflicting evidence, this variant is classified as a variant of unknown significance for autosomal dominant nonsyndromic genetic deafness based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, BS3_P (Hearing Loss VCEP specifications version 2; 6/15/2022).
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
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
Not Met criteria codes
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
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
BA1
The p.Ala119Thr variant is absent from gnomAD. Found in one individual (0.045) in HGVD (Japanese general population).
PM6
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.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The p.Ala119Thr variant is absent from gnomAD. 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.
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
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.
Curation History
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