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

dbSNP: rs121908932

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214849	SCV000271349	pathogenic	Rare genetic deafness	2015-11-24	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001547940	SCV001767763	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	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)
Invitae	RCV001547940	SCV002237040	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000006993	SCV000027189	pathogenic	Autosomal dominant nonsyndromic hearing loss 9	2005-12-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000006993	SCV000536925	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 9	2016-02-29	no assertion criteria provided	research