NM_022124.6(CDH23):c.5647A>C (p.Asn1883His) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Dec 31, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000725133.3

Allele description [Variation Report for NM_022124.6(CDH23):c.5647A>C (p.Asn1883His)]

NM_022124.6(CDH23):c.5647A>C (p.Asn1883His)

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.5647A>C (p.Asn1883His)
HGVS:
  • NC_000010.11:g.71785035A>C
  • NG_008835.1:g.393089A>C
  • NM_022124.6:c.5647A>CMANE SELECT
  • NP_071407.4:p.Asn1883His
  • NC_000010.10:g.73544792A>C
  • NM_022124.5:c.5647A>C
Protein change:
N1883H
Links:
dbSNP: rs747488431
NCBI 1000 Genomes Browser:
rs747488431
Molecular consequence:
  • NM_022124.6:c.5647A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000334353EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Sep 14, 2015)
germlineclinical testing

Citation Link,

SCV000571732GeneDxcriteria provided, single submitter
Uncertain significance
(Oct 4, 2016)
germlineclinical testing

Citation Link,

SCV001212745Invitaecriteria provided, single submitter
Uncertain significance
(Dec 31, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000334353.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From GeneDx, SCV000571732.4

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

Description

The N1883H variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N1883H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1883H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N1883H as a variant of uncertain significance.

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

From Invitae, SCV001212745.1

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

Description

This sequence change replaces asparagine with histidine at codon 1883 of the CDH23 protein (p.Asn1883His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs747488431, ExAC 0.03%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 282746). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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