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NM_001184880.2(PCDH19):c.1342G>A (p.Asp448Asn) AND Developmental and epileptic encephalopathy, 9

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 21, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001231311.7

Allele description [Variation Report for NM_001184880.2(PCDH19):c.1342G>A (p.Asp448Asn)]

NM_001184880.2(PCDH19):c.1342G>A (p.Asp448Asn)

Gene:
PCDH19:protocadherin 19 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq22.1
Genomic location:
Preferred name:
NM_001184880.2(PCDH19):c.1342G>A (p.Asp448Asn)
HGVS:
  • NC_000023.11:g.100407256C>T
  • NG_021319.1:g.8018G>A
  • NM_001105243.2:c.1342G>A
  • NM_001184880.2:c.1342G>AMANE SELECT
  • NM_020766.3:c.1342G>A
  • NP_001098713.1:p.Asp448Asn
  • NP_001171809.1:p.Asp448Asn
  • NP_065817.2:p.Asp448Asn
  • LRG_843t1:c.1342G>A
  • LRG_843:g.8018G>A
  • LRG_843p1:p.Asp448Asn
  • NC_000023.10:g.99662254C>T
  • NM_001184880.1:c.1342G>A
Protein change:
D448N
Links:
dbSNP: rs1569314809
NCBI 1000 Genomes Browser:
rs1569314809
Molecular consequence:
  • NM_001105243.2:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001184880.2:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020766.3:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Developmental and epileptic encephalopathy, 9 (DEE9)
Synonyms:
EPILEPSY, FEMALE-RESTRICTED, WITH MENTAL RETARDATION; JUBERG-HELLMAN SYNDROME; PCDH19-Related X-Linked Female-Limited Epilepsy with Mental Retardation; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010246; MedGen: C1848137; Orphanet: 2076; OMIM: 300088

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001403828Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 21, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Comparative characterization of PCDH19 missense and truncating variants in PCDH19-related epilepsy.

Shibata M, Ishii A, Goto A, Hirose S.

J Hum Genet. 2021 Jun;66(6):569-578. doi: 10.1038/s10038-020-00880-z. Epub 2020 Dec 2.

PubMed [citation]
PMID:
33262389
PMCID:
PMC8144015

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 Invitae, SCV001403828.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp448 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 958194). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 33262389). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 448 of the PCDH19 protein (p.Asp448Asn).

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

Last Updated: Feb 28, 2024