VCV002736106.2 - ClinVar

NM_004086.3(COCH):c.362T>C (p.Phe121Ser)

Germline

Classification

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.

(2)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004086.3(COCH):c.362T>C (p.Phe121Ser)

Variation ID: 2736106 Accession: VCV002736106.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 30878933 (GRCh38) [ NCBI UCSC ] 14: 31348139 (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	Feb 14, 2024	May 1, 2024	Apr 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004086.3:c.362T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004077.1:p.Phe121Ser	missense
NM_001135058.2:c.362T>C	NP_001128530.1:p.Phe121Ser	missense
NM_001347720.2:c.557T>C	NP_001334649.1:p.Phe186Ser	missense
NC_000014.9:g.30878933T>C
NC_000014.8:g.31348139T>C
NG_008211.2:g.9399T>C
NG_008211.3:g.9376T>C

... more HGVS ... less HGVS

Protein change

F121S, F186S

Other names

Canonical SPDI

NC_000014.9:30878932:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

VarSome

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
Gene	OMIM	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	39	290
LOC100506071	-	-	-	GRCh38	-	233

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 6, 2023	RCV003557821.2
Autosomal dominant nonsyndromic hearing loss 9	Pathogenic (1)	criteria provided, single submitter	Apr 22, 2024	RCV004369277.2

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 (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004296332.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 21046548‚ 25230692 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 121 of the COCH protein (p.Phe121Ser). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 121 of the COCH protein (p.Phe121Ser). 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: 21046548). It has also been observed to segregate with disease in related individuals. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects COCH function (PMID: 25230692). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 9 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004849386.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Clinical Features: Tinnitus (present) , Sensorineural hearing loss disorder (present) , Transient hearing impairment (present)

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 121 of the COCH protein (p.Phe121Ser). 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: 21046548). It has also been observed to segregate with disease in related individuals. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects COCH function (PMID: 25230692). For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder.	Bae SH	Human mutation	2014	PMID: 25230692
A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss.	Hildebrand MS	The Laryngoscope	2010	PMID: 21046548

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_004086.3(COCH):c.362T>C (p.Phe121Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...