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NM_001184880.2(PCDH19):c.824A>G (p.Tyr275Cys) AND Developmental and epileptic encephalopathy, 9

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 10, 2023
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:
RCV001368904.7

Allele description [Variation Report for NM_001184880.2(PCDH19):c.824A>G (p.Tyr275Cys)]

NM_001184880.2(PCDH19):c.824A>G (p.Tyr275Cys)

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.824A>G (p.Tyr275Cys)
HGVS:
  • NC_000023.11:g.100407774T>C
  • NG_021319.1:g.7500A>G
  • NM_001105243.2:c.824A>G
  • NM_001184880.2:c.824A>GMANE SELECT
  • NM_020766.3:c.824A>G
  • NP_001098713.1:p.Tyr275Cys
  • NP_001171809.1:p.Tyr275Cys
  • NP_065817.2:p.Tyr275Cys
  • LRG_843t1:c.824A>G
  • LRG_843:g.7500A>G
  • LRG_843p1:p.Tyr275Cys
  • NC_000023.10:g.99662772T>C
Protein change:
Y275C
Links:
dbSNP: rs1928426496
NCBI 1000 Genomes Browser:
rs1928426496
Molecular consequence:
  • NM_001105243.2:c.824A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001184880.2:c.824A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020766.3:c.824A>G - 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
SCV001565323Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 10, 2023) 		germlineclinical testing

PubMed (3)
[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

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study.

Epi4K consortium.; Epilepsy Phenome/Genome Project..

Lancet Neurol. 2017 Feb;16(2):135-143. doi: 10.1016/S1474-4422(16)30359-3.

PubMed [citation]
PMID:
28102150

Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders.

van Harssel JJ, Weckhuysen S, van Kempen MJ, Hardies K, Verbeek NE, de Kovel CG, Gunning WB, van Daalen E, de Jonge MV, Jansen AC, Vermeulen RJ, Arts WF, Verhelst H, Fogarasi A, de Rijk-van Andel JF, Kelemen A, Lindhout D, De Jonghe P, Koeleman BP, Suls A, Brilstra EH.

Neurogenetics. 2013 Feb;14(1):23-34. doi: 10.1007/s10048-013-0353-1. Epub 2013 Jan 20.

PubMed [citation]
PMID:
23334464
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001565323.4

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 275 of the PCDH19 protein (p.Tyr275Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with non-acquired focal epilepsy (PMID: 28102150). ClinVar contains an entry for this variant (Variation ID: 806009). 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. This variant disrupts the p.Tyr275 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been observed in individuals with PCDH19-related conditions (PMID: 23334464), which suggests that this may be a clinically significant amino acid residue. 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: Sep 29, 2024