chr14-30877640-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PP1_StrongPM2PP3
This summary comes from the ClinGen Evidence Repository: The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID:9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID:28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253889/MONDO:0019497/005
Frequency
Consequence
NM_004086.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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Nonsyndromic genetic hearing loss Pathogenic:1
The c.151C>T (p.Pro51Ser) variant in COCH has been reported to segregate with late onset progressive hearing loss and vestibular dysfunction in > 25 family members (PP1_S; PMID: 9931344, 11332404). The variant meets PM2 and has been observed in at least 15 affected probands (PS4, PMID: 28733840, 16151338, 11332404). The allele frequency of the p.Pro51Ser variant is 0.001% (1/111716) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant hearing loss (PM2). Computational prediction tools and conservation analysis suggest that the p.Pro51Ser variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_S, PS4, PM2, PP3. -
Hearing impairment Pathogenic:1
PS1_Strong, PM2_Moderate, PP3_Supporting -
Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:1
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Rare genetic deafness Pathogenic:1
The Pro51Ser variant in COCH has segregated in many Dutch families with late ons et autosomal dominant progressive sensorineural hearing loss with vestibular def ects (Bischoff 2005, de Kok 1999, Fransen 2001). It has been suggested that this variant is likely a found mutation in the Dutch population. In summary, this va riant meets our criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at