ClinVar Genomic variation as it relates to human health
NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)
Variation ID: 6614 Accession: VCV000006614.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q12 14: 30889763 (GRCh38) [ NCBI UCSC ] 14: 31358969 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Feb 14, 2024 Dec 1, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004086.3:c.1625G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004077.1:p.Cys542Phe missense NM_001135058.2:c.1625G>T NP_001128530.1:p.Cys542Phe missense NM_001347720.2:c.1820G>T NP_001334649.1:p.Cys607Phe missense NR_038356.1:n.46C>A non-coding transcript variant NC_000014.9:g.30889763G>T NC_000014.8:g.31358969G>T NG_008211.2:g.20229G>T - Protein change
- C542F, C607F
- Other names
- -
- Canonical SPDI
- NC_000014.9:30889762:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
COCH | - | - |
GRCh38 GRCh37 |
33 | 268 | |
LOC100506071 | - | - | - | GRCh38 | - | 216 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Feb 29, 2016 | RCV000006993.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 24, 2015 | RCV000214849.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV001547940.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271349.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Cys542Phe variant in COCH has been reported in one family with post-lingua l progressive sensorineural hearing loss, in which the variant segregated with h … (more)
The p.Cys542Phe variant in COCH has been reported in one family with post-lingua l progressive sensorineural hearing loss, in which the variant segregated with h earing loss in 15 affected relatives in an autosomal dominant pattern (Street 20 05). In addition, this variant was absent from large population studies and two other variants (p.Cys542Arg, p.Cys542Tyr) affecting the same position have also been reported in families with dominant hearing loss (Yuan 2008, Tsukada 2015) i ndicating that this position is intolerant to variation. In summary, this varian t meets our criteria to be classified as pathogenic for hearing loss in an autos omal dominant manner based on segregation data and absence in controls. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001767763.2
First in ClinVar: Aug 07, 2021 Last updated: Jan 21, 2023 |
Comment:
Reported by exome sequencing in a proband with mild bilateral sensorineural hearing loss, but age-of-onset and segregation information were not provided (Sheppard et al., 2018); … (more)
Reported by exome sequencing in a proband with mild bilateral sensorineural hearing loss, but age-of-onset and segregation information were not provided (Sheppard et al., 2018); This variant was found significantly more frequently in cases with ICD10 codes for hearing loss vs. controls in a large association study; the authors suggested that the presence in the two controls may be explained by either imperfect ascertainment of the phenotype or variable expressivity (Praveen et al., 2022); A meta-analysis on published cases with variants in the COCH gene suggested that p.C542F was associated with an earlier age-of-onset than the other variants evaluated based on non-linear regression analysis of audiometric data (Robijn et al., 2022); Published functional studies demonstrate a damaging effect: reduced binding affinity to N-sulfated heparin (Honda et al., 2022); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16261627, 35901072, 35661827, 29907799, 35204720) (less)
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002237040.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 542 of the COCH protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 542 of the COCH protein (p.Cys542Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 16261627). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6614). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COCH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COCH function (PMID: 16261627). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Feb 29, 2016)
|
no assertion criteria provided
Method: research
|
Autosomal dominant nonsyndromic hearing loss 9
Affected status: yes
Allele origin:
paternal
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536925.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
Pathogenic
(Dec 01, 2005)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL DOMINANT 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027189.3
First in ClinVar: Apr 04, 2013 Last updated: May 03, 2018 |
Comment on evidence:
In an American pedigree (HL3) with hearing loss and vestibular disturbances (DFNA9; 601369), as well as oculomotor disturbances, Street et al. (2005) identified a 1625G-T … (more)
In an American pedigree (HL3) with hearing loss and vestibular disturbances (DFNA9; 601369), as well as oculomotor disturbances, Street et al. (2005) identified a 1625G-T transversion in exon 12 of the COCH gene, resulting in cys542-to-phe (C542F) substitution at the C terminus of cochlin. The mutation cosegregated with auditory dysfunction and was not found in 206 control chromosomes. Hearing loss and vestibular dysfunction was present in a 17-year-old male in this family; Street et al. (2005) stated that this was the youngest reported age of onset in a DFNA9 family member to date. (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Detailed hearing and vestibular profiles in the patients with COCH mutations. | Tsukada K | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25780252 |
Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families. | Yuan HJ | Clinical genetics | 2008 | PMID: 18312449 |
A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. | Street VA | American journal of medical genetics. Part A | 2005 | PMID: 16261627 |
Text-mined citations for rs121908932 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.