NM_022124.6(CDH23):c.2236G>A (p.Val746Ile) AND Autosomal recessive nonsyndromic hearing loss 12

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 2, 2022
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:: RCV001105264.5

Allele description [Variation Report for NM_022124.6(CDH23):c.2236G>A (p.Val746Ile)]

NM_022124.6(CDH23):c.2236G>A (p.Val746Ile)

Gene:

CDH23:cadherin related 23 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_022124.6(CDH23):c.2236G>A (p.Val746Ile)

HGVS:

NC_000010.11:g.71694206G>A
NG_008835.1:g.302260G>A
NM_001171930.2:c.2236G>A
NM_001171931.2:c.2236G>A
NM_022124.6:c.2236G>AMANE SELECT
NP_001165401.1:p.Val746Ile
NP_001165402.1:p.Val746Ile
NP_071407.4:p.Val746Ile
NC_000010.10:g.73453963G>A
NM_022124.5:c.2236G>A

Protein change:

V746I

Links:

dbSNP: rs550384315

NCBI 1000 Genomes Browser:

rs550384315

Molecular consequence:

NM_001171930.2:c.2236G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001171931.2:c.2236G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_022124.6:c.2236G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 12
Synonyms:: Deafness, autosomal recessive 12
Identifiers:: MONDO: MONDO:0011067; MedGen: C1832394; Orphanet: 90636; OMIM: 601386

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001262204	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link,
SCV002767256	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31054281, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001262204

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

Citation Link,

SCV002767256

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

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

Genetic and Clinical Findings in a Large Cohort of Chinese Patients with Suspected Retinitis Pigmentosa.

Gao FJ, Li JK, Chen H, Hu FY, Zhang SH, Qi YH, Xu P, Wang DD, Wang LS, Chang Q, Zhang YJ, Liu W, Li W, Wang M, Chen F, Xu GZ, Wu JH.

Ophthalmology. 2019 Nov;126(11):1549-1556. doi: 10.1016/j.ophtha.2019.04.038. Epub 2019 May 1. Erratum in: Ophthalmology. 2020 Mar;127(3):434. doi: 10.1016/j.ophtha.2019.12.013.

PubMed [citation]

PMID:: 31054281

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001262204.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767256.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 12 (MIM#601386) and Usher syndrome type 1D (MIM#601067). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (30 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Cadherin domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Val746Leu) variant has been reported as unknown significance (Deafness Variation Database). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as uncertain significance, likely benign and benign in ClinVar. It has also been reported as likely pathogenic in an individual with retinal dystrophy who is also heterozygous for another missense variant in CDH23 and 2 variants in TTLL5 gene (PMID: 31054281, LOVD, Deafness Variation Database). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Sep 29, 2024

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