NM_022124.6(CDH23):c.5945A>G (p.Asn1982Ser) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Aug 22, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000483578.2

Allele description [Variation Report for NM_022124.6(CDH23):c.5945A>G (p.Asn1982Ser)]

NM_022124.6(CDH23):c.5945A>G (p.Asn1982Ser)

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.5945A>G (p.Asn1982Ser)
HGVS:
  • NC_000010.11:g.71790309A>G
  • NG_008835.1:g.398363A>G
  • NM_022124.6:c.5945A>GMANE SELECT
  • NP_071407.4:p.Asn1982Ser
  • NC_000010.10:g.73550066A>G
  • NM_022124.5:c.5945A>G
Protein change:
N1982S
Links:
dbSNP: rs555432123
NCBI 1000 Genomes Browser:
rs555432123
Molecular consequence:
  • NM_022124.6:c.5945A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000571379GeneDxcriteria provided, single submitter
Uncertain significance
(Aug 18, 2016)
germlineclinical testing

Citation Link,

SCV001421834Invitaecriteria provided, single submitter
Uncertain significance
(Aug 22, 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 providedgermlineunknownnot providednot 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 GeneDx, SCV000571379.3

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

Description

The N1982S variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N1982S variant was not observed in approximately 6,300 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 N1982S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N1982S as a variant of uncertain significance.

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

From Invitae, SCV001421834.1

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

Description

This sequence change replaces asparagine with serine at codon 1982 of the CDH23 protein (p.Asn1982Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs555432123, ExAC 0.009%). This variant has not been reported in the literature in individuals with CDH23-related disease. ClinVar contains an entry for this variant (Variation ID: 422021). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: Oct 8, 2021

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