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NM_022124.6(CDH23):c.6049G>A (p.Gly2017Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(4);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Sep 30, 2021)
Last evaluated:
Jul 13, 2021
Accession:
VCV000046000.5
Variation ID:
46000
Description:
single nucleotide variant
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NM_022124.6(CDH23):c.6049G>A (p.Gly2017Ser)

Allele ID
55165
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
10q22.1
Genomic location
10: 71790413 (GRCh38) GRCh38 UCSC
10: 73550170 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000010.10:g.73550170G>A
NC_000010.11:g.71790413G>A
NG_008835.1:g.398467G>A
NM_022124.6:c.6049G>A MANE Select NP_071407.4:p.Gly2017Ser missense
Protein change
G2017S
Other names
-
Canonical SPDI
NC_000010.11:71790412:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00003
Links
ClinGen: CA261792
dbSNP: rs183431253
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 4 criteria provided, multiple submitters, no conflicts Jul 13, 2021 RCV001377826.4
Likely pathogenic 1 criteria provided, single submitter Nov 23, 2011 RCV000039235.2
Likely pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763216.1
Uncertain significance 1 criteria provided, single submitter Apr 8, 2021 RCV001376240.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CDH23 - - GRCh38
GRCh37
2168 2608

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Jul 13, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001812919.1
Submitted: (Aug 31, 2021)
Evidence details
Comment:
Published functional studies demonstrate a damaging splicing effect with skipping of exon 46 likely resulting in nonsense-mediated decay (Aparisi et al., 2013); In silico analysis … (more)
Likely pathogenic
(Nov 23, 2011)
criteria provided, single submitter
Method: clinical testing
Rare genetic deafness
(Autosomal recessive inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000062919.5
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (2)
Comment:
The Gly2017Ser variant in CDH23 has been reported in 2 probands with Usher synd rome type I and was absent from 192 control chromosomes (Oshima … (more)
Likely pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Usher syndrome type 1D
Deafness, autosomal recessive 12
Pituitary adenoma 5, multiple types
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893842.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Likely pathogenic
(May 20, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV001575261.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces glycine with serine at codon 2017 of the CDH23 protein (p.Gly2017Ser). The glycine residue is highly conserved and there is a … (more)
Uncertain significance
(Apr 08, 2021)
criteria provided, single submitter
Method: research
Usher syndrome type 1D
Allele origin: germline
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573313.1
Submitted: (Apr 26, 2021)
Evidence details
Publications
PubMed (3)
Comment:
The CDH23 c.6049G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Clinical Genetics,Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921507.1
Submitted: (Sep 23, 2021)
Evidence details
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Human Genetics - Radboudumc,Radboudumc
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953094.1
Submitted: (Sep 30, 2021)
Evidence details

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
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 Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Xiong HY Science (New York, N.Y.) 2015 PMID: 25525159
Targeted next generation sequencing for molecular diagnosis of Usher syndrome. Aparisi MJ Orphanet journal of rare diseases 2014 PMID: 25404053
Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells. Aparisi MJ PloS one 2013 PMID: 23451239
Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Oshima A Human mutation 2008 PMID: 18429043
[Usher type I syndrome in children: genotype/phenotype correlation and cochlear implant benefits]. Blanchet C Revue de laryngologie - otologie - rhinologie 2007 PMID: 18323324
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Buratti E Nucleic acids research 2007 PMID: 17576681
Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. Roux AF Journal of medical genetics 2006 PMID: 16679490
Statistical features of human exons and their flanking regions. Zhang MQ Human molecular genetics 1998 PMID: 9536098

Text-mined citations for rs183431253...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021