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  • No ClinVar Id was directly found from the curated document


CA1563057

Gene: OTOF
Condition: autosomal recessive nonsyndromic deafness 9
Inheritance Mode: Autosomal recessive inheritance
UUID: 42cb25c9-af9e-4a41-8e82-25e04ca787fc
Approved on: 2022-08-03
Published on: 2022-08-03

HGVS expressions

NM_194323.3:c.2447G>A
NC_000002.12:g.26465723C>T
CM000664.2:g.26465723C>T
NC_000002.11:g.26688591C>T
CM000664.1:g.26688591C>T
NC_000002.10:g.26542095C>T
NG_009937.1:g.97976G>A
ENST00000272371.7:c.4748G>A
ENST00000339598.8:c.2447G>A
ENST00000402415.8:c.2507G>A
ENST00000272371.6:c.4748G>A
ENST00000338581.10:c.2447G>A
ENST00000339598.7:c.2447G>A
ENST00000402415.7:c.2678G>A
ENST00000403946.7:c.4748G>A
ENST00000464574.1:n.497G>A
NM_001287489.1:c.4748G>A
NM_004802.3:c.2447G>A
NM_194248.2:c.4748G>A
NM_194322.2:c.2678G>A
NM_194323.2:c.2447G>A
NM_001287489.2:c.4748G>A
NM_004802.4:c.2447G>A
NM_194248.3:c.4748G>A
NM_194322.3:c.2678G>A
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Likely Pathogenic

Met criteria codes 5
PM3 PM5 PP4 PP3 PM2_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.4748G>A variant in OTOF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1583. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16254 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). Another missense variant c.4747C>T (p.R1583C) (PMID:26818607, 31589614, 32747562, 33724713, 34426522, ClinVar Variation ID:402270) in the same codon has been classified as pathogenic/likely pathogenic for autosomal recessive nonsyndromic hearing loss in ClinVar (PM5). At least one patient with this variant and compound heterozygous for the c.2215-1G>C variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for ANSD (PP4, PMID:24001616). This variant has been detected in at least 1 individual with ANSD, who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant were confirmed in trans by family testing (c.2215-1G>C, 1 PM3 point, PMID:24001616). Additional compound heterozygous cases with variants c.5816G>A (p.R1939Q), c.3515G>A (p.R1172Q), and c.2523+1G>T (PMIDs: 24053799, 31095577, 31827501 respectively) were also seen, but excluded from scoring due to less scorable evidence. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PM5, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022).
Met criteria codes
PM3
This variant has been detected in at least 1 individual with ANSD, who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant were confirmed in trans by family testing (c.2215-1G>C, 1 PM3 point, PMID:24001616). Additional compound heterozygous cases with variants c.5816G>A (p.R1939Q), c.3515G>A (p.R1172Q), and c.2523+1G>T (PMIDs: 24053799, 31095577, 31827501 respectively) were also seen, but excluded from scoring due to less scorable evidence.
PM5
Another missense variant c.4747C>T (p.R1583C) (PMID:26818607, 31589614, 32747562, 33724713, 34426522, ClinVar Variation ID:402270) in the same codon has been classified as pathogenic/likely pathogenic for autosomal recessive nonsyndromic hearing loss in ClinVar (PM5).
PP4
At least one patient was compound heterozygous for this variant and displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for ANSD (PP4, PMID:23208854).
PP3
The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16254 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting).
Curation History
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