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NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val) AND not specified

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Sep 13, 2023
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:
RCV000039313.9

Allele description [Variation Report for NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)]

NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)

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.9569C>T (p.Ala3190Val)
HGVS:
  • NC_000010.11:g.71812826C>T
  • NG_008835.1:g.420880C>T
  • NM_001171933.1:c.2849C>T
  • NM_001171934.1:c.2849C>T
  • NM_001171935.1:c.260C>T
  • NM_001171936.1:c.260C>T
  • NM_022124.6:c.9569C>TMANE SELECT
  • NP_001165404.1:p.Ala950Val
  • NP_001165405.1:p.Ala950Val
  • NP_001165406.1:p.Ala87Val
  • NP_001165407.1:p.Ala87Val
  • NP_071407.4:p.Ala3190Val
  • NC_000010.10:g.73572583C>T
  • NM_022124.5:c.9569C>T
  • NM_022124.6(CDH23):c.9569C>TMANE SELECT
  • c.9569C>T
Protein change:
A3190V
Links:
dbSNP: rs111033536
NCBI 1000 Genomes Browser:
rs111033536
Molecular consequence:
  • NM_001171933.1:c.2849C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171934.1:c.2849C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171935.1:c.260C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171936.1:c.260C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022124.6:c.9569C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000062997Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Uncertain significance
(Sep 12, 2017) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002500713Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Sep 13, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided44not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Genomic Landscape and Mutational Signatures of Deafness-Associated Genes.

Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, Shearer AE, Sloan-Heggen CM, Kolbe D, Casavant T, Schnieders MJ, Nishimura C, Braun T, Smith RJH.

Am J Hum Genet. 2018 Oct 4;103(4):484-497. doi: 10.1016/j.ajhg.2018.08.006. Epub 2018 Sep 20.

PubMed [citation]
PMID:
30245029
PMCID:
PMC6174355
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000062997.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (3)

Description

The p.Ala3190Val variant in CDH23 has been reported in 1 individual with Usher s yndrome who also had a duplication of exon 29 in CDH23 that is of uncertain sign ificance (Aparisi 2014), and in 1 individual with hearing loss who also had the p.Arg3206Cys variant of uncertain significance in CDH23 (Sommen 2016). The p.Ala 3190Val variant has also been identified by our laboratory in the heterozygous s tate in 3 individuals with hearing loss; however, a variant affecting the remain ing copy of CDH23 was not identified in any of these individuals. This variant h as been identified in 0.08% (8/10122) of Ashkenazi Jewish chromosomes and 0.05% (64/126200) European chromosomes by Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs111033536). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Ala3190Val variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided4not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500713.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: CDH23 c.9569C>T (p.Ala3190Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247998 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00034 vs 0.0032), allowing no conclusion about variant significance. c.9569C>T has been reported in the literature in individuals with hearing loss (e.g., Aparisi_2014, Sommen_2016, Clabout_2022), however without strong evidence of causality in all cases (e.g., lack of a second confirmed CDH23 allele and/or segregation/phase not determined). This variant was also listed as an expert curated classification of "likely pathogenic" in the Deafness Variation Database (DVD) (e.g., Azaiez_2018) and cited by others (e.g., Chen_2019). These reports therefore do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25404053, 30245029, 27068579, 36672845, 31445392). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; Likely pathogenic, n=1; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 24, 2024