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]
  • See Evidence submitted by expert panel for details.

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: 2018-09-17
Published on: 2019-07-17

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
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Uncertain Significance

Met criteria codes 2
PM2 BS3_Supporting
Not Met criteria codes 24
PP1 PP2 PP3 PP4 PM1 PM3 PM5 PM4 PM6 PVS1 BA1 BS2 BS1 BS4 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PS3 PS4

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.355G>A (p.Ala119Thr) variant in COCH has been reported in one Japanese individual with hearing loss, vestibular dysfunction, and a family history of hearing loss though no other affected family members were screened (PS4 not met; PMID: 14512963). The variant was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). A functional study demonstrates that this variant may not impact protein function (BS3_P; PMID: 25230692). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, BS3_P.
Met criteria codes
PM2
The p.Ala119Thr variant is absent from gnomAD. Found in one individual (0.045) in HGVD (Japanese general population). - Alex C
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
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.
PP4
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
PM3
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
PM6
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
BA1
The p.Ala119Thr variant is absent from gnomAD. Found in one individual (0.045) in HGVD (Japanese general population). - Alex C
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. - Alex C
BS1
The p.Ala119Thr variant is absent from gnomAD. Found in one individual (0.045) in HGVD (Japanese general population). - Alex C
BS4
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
BP7
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.
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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.
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
Curation History
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