rs121908933

Positions:

• chr14-30889763-G-T
• chr14-30889763-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004086.3(COCH):​c.1625G>T​(p.Cys542Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C542Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COCH NM_004086.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.49

Genes affected

COCH (HGNC:2180): (cochlin) The protein encoded by this gene is highly conserved in human, mouse, and chicken, showing 94% and 79% amino acid identity of human to mouse and chicken sequences, respectively. Hybridization to this gene was detected in spindle-shaped cells located along nerve fibers between the auditory ganglion and sensory epithelium. These cells accompany neurites at the habenula perforata, the opening through which neurites extend to innervate hair cells. This and the pattern of expression of this gene in chicken inner ear paralleled the histologic findings of acidophilic deposits, consistent with mucopolysaccharide ground substance, in temporal bones from DFNA9 (autosomal dominant nonsyndromic sensorineural deafness 9) patients. Mutations that cause DFNA9 have been reported in this gene. Alternative splicing results in multiple transcript variants encoding the same protein. Additional splice variants encoding distinct isoforms have been described but their biological validities have not been demonstrated. [provided by RefSeq, Oct 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-30889762-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1185584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 14-30889763-G-T is Pathogenic according to our data. Variant chr14-30889763-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 6614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-30889763-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COCH	NM_004086.3	c.1625G>T	p.Cys542Phe	missense_variant	12/12	ENST00000396618.9
LOC100506071	NR_038356.1	n.46C>A		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COCH	ENST00000396618.9	c.1625G>T	p.Cys542Phe	missense_variant	12/12	1	NM_004086.3	P1
	ENST00000555108.1	n.46C>A		non_coding_transcript_exon_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2022	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) -

Autosomal dominant nonsyndromic hearing loss 9 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 29, 2016	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;D;D;T;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;.;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.5	.;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.6	.;D;.;D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Pathogenic	0.0	.;D;.;D;.
Polyphen		0.57	.;P;P;.;P
Vest4		0.95, 0.98
MutPred		0.99		.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);
MVP		0.93
MPC		1.0
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908932; hg19: chr14-31358969;