NM_004086.3(COCH):c.1625G>T (p.Cys542Phe) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001547940.8

Allele description [Variation Report for NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)]

NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)

Genes:

COCH:cochlin [Gene - OMIM - HGNC]
LOC100506071:uncharacterized LOC100506071 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

14q12

Genomic location:

Preferred name:

NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)

HGVS:

NC_000014.9:g.30889763G>T
NG_008211.2:g.20229G>T
NM_001135058.2:c.1625G>T
NM_001347720.2:c.1820G>T
NM_004086.3:c.1625G>TMANE SELECT
NP_001128530.1:p.Cys542Phe
NP_001334649.1:p.Cys607Phe
NP_004077.1:p.Cys542Phe
NC_000014.8:g.31358969G>T
NM_004086.2:c.1625G>T
NR_038356.1:n.46C>A

Protein change:

C542F; CYS542PHE

Links:

OMIM: 603196.0007; dbSNP: rs121908932

NCBI 1000 Genomes Browser:

rs121908932

Molecular consequence:

NM_001135058.2:c.1625G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001347720.2:c.1820G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004086.3:c.1625G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_038356.1:n.46C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001767763	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 6, 2022)	germline	clinical testing	Citation Link,
SCV002237040	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16261627, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001767763

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 6, 2022)

germline

clinical testing

Citation Link,

SCV002237040

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Kallman JC, Robertson NG, Kuo SF, Morton CC, Phillips JO.

Am J Med Genet A. 2005 Dec 1;139A(2):86-95.

PubMed [citation]

PMID:: 16261627

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001767763.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002237040.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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