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]

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Variant: NM_194248.2(OTOF):c.5098G>C

CA345132

48253 (ClinVar)

Gene: OTOF

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a3a44624-d639-4324-a887-81890dc4927c

HGVS expressions

NM_194248.2(OTOF):c.5098G>C

NC_000002.12:g.26463969C>G

CM000664.2:g.26463969C>G

NC_000002.11:g.26686837C>G

CM000664.1:g.26686837C>G

NC_000002.10:g.26540341C>G

NG_009937.1:g.99730G>C

ENST00000272371.7:c.5098G>C

ENST00000339598.8:c.2797G>C

ENST00000402415.8:c.2857G>C

ENST00000272371.6:c.5098G>C

ENST00000338581.10:c.2797G>C

ENST00000339598.7:c.2797G>C

ENST00000402415.7:c.3028G>C

ENST00000403946.7:c.5098G>C

ENST00000464574.1:n.847G>C

NM_001287489.1:c.5098G>C

NM_004802.3:c.2797G>C

NM_194248.2:c.5098G>C

NM_194322.2:c.3028G>C

NM_194323.2:c.2797G>C

NM_001287489.2:c.5098G>C

NM_004802.4:c.2797G>C

NM_194248.3:c.5098G>C

NM_194322.3:c.3028G>C

NM_194323.3:c.2797G>C

Uncertain Significance

PP1 PP4 PP3 PM3

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the c.5098G>C (p.Glu1700Gln) variant in the OTOF gene is 0.5935% for East Asian chromosomes with one homozygote in gnomAD. This is a high enough frequency that might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. This variant has been detected in 21 individuals with autosomal recessive nonsyndromic hearing loss. For 2 of those patients, a pathogenic or suspected-pathogenic variant was observed in trans, and in 6 the variant was observed in the homozygous state (PM3; PMID: 30368385, 20224275, 28766844). The variant has been reported to segregate with hearing loss in two affected family members (PP1, PMID: 20224275). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4). The REVEL computational prediction analysis tool produced a score of 0.85, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3, PP1, PP4, PP3.

PP1

1 affected segregation in a family with 2 homozygous siblings

PP4

Significantly increased percent of patients with HL with ANSD than HL without ANSD.

PP3

The REVEL computational prediction analysis tool produced a score of 0.85, which is above the threshold necessary to apply PP3 (0.7)

PM3

1.75 PM3 points total for max score of 1 point for homozygous occurrences and 0.75 points of a compound heterozygous occurrence with a pathogenic variant but without phase confirmation.

Approved on: 2021-06-23

Published on: 2022-05-13

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