NM_022124.6(CDH23):c.6050-9G>A AND not provided

Clinical significance:Pathogenic (Last evaluated: Oct 23, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000239237.8

Allele description [Variation Report for NM_022124.6(CDH23):c.6050-9G>A]

NM_022124.6(CDH23):c.6050-9G>A

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.6050-9G>A
HGVS:
  • NC_000010.11:g.71791123G>A
  • NG_008835.1:g.399177G>A
  • NM_022124.6:c.6050-9G>AMANE SELECT
  • NC_000010.10:g.73550880G>A
  • NM_022124.5:c.6050-9G>A
  • c.6050-9G>A
Links:
dbSNP: rs367928692
NCBI 1000 Genomes Browser:
rs367928692
Molecular consequence:
  • NM_022124.6:c.6050-9G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000297306Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphiacriteria provided, single submitter
Pathogenic
(Aug 10, 2015)
unknownclinical testing

DGD_Variant_Analysis_Guidelines.docx,

Citation Link,

SCV000329238GeneDxcriteria provided, single submitter
Pathogenic
(Sep 27, 2016)
germlineclinical testing

Citation Link,

SCV001389693Invitaecriteria provided, single submitter
Pathogenic
(Sep 21, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001446876Institute of Medical Genetics and Applied Genomics, University Hospital Tübingencriteria provided, single submitter
Pathogenic
(Oct 23, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001924494Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedPathogenicgermlineclinical testing

SCV001959225Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedPathogenicgermlineclinical testing

SCV001975840Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedPathogenicgermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.

Schultz JM, Bhatti R, Madeo AC, Turriff A, Muskett JA, Zalewski CK, King KA, Ahmed ZM, Riazuddin S, Ahmad N, Hussain Z, Qasim M, Kahn SN, Meltzer MR, Liu XZ, Munisamy M, Ghosh M, Rehm HL, Tsilou ET, Griffith AJ, Zein WM, Brewer CC, et al.

J Med Genet. 2011 Nov;48(11):767-75. doi: 10.1136/jmedgenet-2011-100262. Epub 2011 Sep 22.

PubMed [citation]
PMID:
21940737

Targeted next generation sequencing for molecular diagnosis of Usher syndrome.

Aparisi MJ, Aller E, Fuster-García C, García-García G, Rodrigo R, Vázquez-Manrique RP, Blanco-Kelly F, Ayuso C, Roux AF, Jaijo T, Millán JM.

Orphanet J Rare Dis. 2014 Nov 18;9:168. doi: 10.1186/s13023-014-0168-7.

PubMed [citation]
PMID:
25404053
PMCID:
PMC4245769
See all PubMed Citations (10)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia, SCV000297306.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV000329238.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.6050-9 G>A splice site variant in the CDH23 gene has been reported previously in association with Usher syndrome type ID (von Brederlow et al., 2002; Besnard et al., 2014), using alternate nomenclature as IVS45-9 G>A. Von Brederlow and colleagues report on several patients who are heterozygous for this variant, and one who is homozygous. The G>A substitution is predicted to create a novel acceptor splice site 9 bp upstream from the 5' end of exon 46, which results in an insertion of 7 bp at the 3' end of intron 45. The c.6050-9 G>A variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Given the available evidence, we interpret c.6050-9 G>A as a pathogenic variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001389693.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change falls in intron 46 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. This variant is present in population databases (rs367928692, ExAC 0.02%). This variant has been reported to segregate with Usher syndrome type I in several families (PMID: 11857743, 21940737). This variant has also been reported as homozygous or in combination with another CDH23 variant in many individuals with Usher syndrome type I (PMID: 11857743, 25404053, 18429043, 21569298, 12075507, 17407589). ClinVar contains an entry for this variant (Variation ID: 46001). This variant is also known as IVS45-9G>A in the literature. Experimental studies have shown that this intronic change results in aberrant splicing (PMID: 11857743, 20513143). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446876.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot providednot providednot providednot providednot provided

From Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus, SCV001924494.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus, SCV001959225.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001975840.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 6, 2021

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