NM_001184880.2(PCDH19):c.1091dup (p.Tyr366fs) AND Developmental and epileptic encephalopathy, 9

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jun 9, 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:: RCV000173240.13

Allele description [Variation Report for NM_001184880.2(PCDH19):c.1091dup (p.Tyr366fs)]

NM_001184880.2(PCDH19):c.1091dup (p.Tyr366fs)

Gene:

PCDH19:protocadherin 19 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_001184880.2(PCDH19):c.1091dup (p.Tyr366fs)

HGVS:

NC_000023.11:g.100407513dup
NG_021319.1:g.7767dup
NM_001105243.2:c.1091dup
NM_001184880.2:c.1091dupMANE SELECT
NM_020766.3:c.1091dup
NP_001098713.1:p.Tyr366fs
NP_001171809.1:p.Tyr366fs
NP_065817.2:p.Tyr366fs
LRG_843t1:c.1091dup
LRG_843:g.7767dup
LRG_843p1:p.Tyr366fs
NC_000023.10:g.99662504_99662505insG
NC_000023.10:g.99662511dup
NC_000023.11:g.100407506_100407507insG
NM_001105243.1:c.1091dupC
NM_001184880.1:c.1091dup
NM_001184880.1:c.1091dupC
p.Y366LfsX10

Protein change:

Y366fs

Links:

OMIM: 300460.0001; dbSNP: rs758946412

NCBI 1000 Genomes Browser:

rs758946412

Molecular consequence:

NM_001105243.2:c.1091dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001184880.2:c.1091dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_020766.3:c.1091dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031994	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 5116697, 18469813
SCV000548732	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18469813, 22267240, 22946748, 23334464, 27143072, 27527380, 21053371, 28492532
SCV000782225	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002517857	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A new familial form of convulsive disorder and mental retardation limited to females.

Juberg RC, Hellman CD.

J Pediatr. 1971 Nov;79(5):726-32. No abstract available.

PubMed [citation]

PMID:: 5116697

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.

Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones D, Lee R, Madison M, et al.

Nat Genet. 2008 Jun;40(6):776-81. doi: 10.1038/ng.149. Epub 2008 May 11.

PubMed [citation]

PMID:: 18469813
PMCID:: PMC2756413

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000031994.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected females of the original family with female-restricted epilepsy with mental retardation, also known as developmental and epileptic encephalopathy-9 (DEE9; 300088), reported by Juberg and Hellman (1971), Dibbens et al. (2008) identified a heterozygous 1-bp insertion (1091_1092insC) in the PCDH19 gene, resulting in a frameshift and premature termination of the protein in the extracellular domain. The mutation was predicted to result in complete loss of function. The mutation was not detected in 750 control chromosomes and segregated with the disorder. The age at onset of epilepsy in the patients ranged from 6 to 18 months.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000548732.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This premature translational stop signal has been observed in individual(s) with epilepsy and intellectual disability (PMID: 18469813, 22267240, 22946748, 23334464, 27143072, 27527380). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr366Leufs*10) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). ClinVar contains an entry for this variant (Variation ID: 206353). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782225.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002517857.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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