NM_001184880.2(PCDH19):c.1549G>A (p.Ala517Thr) AND Developmental and epileptic encephalopathy, 9

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV001089700.5

Allele description [Variation Report for NM_001184880.2(PCDH19):c.1549G>A (p.Ala517Thr)]

NM_001184880.2(PCDH19):c.1549G>A (p.Ala517Thr)

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.1549G>A (p.Ala517Thr)

HGVS:

NC_000023.11:g.100407049C>T
NG_021319.1:g.8225G>A
NM_001105243.2:c.1549G>A
NM_001184880.2:c.1549G>AMANE SELECT
NM_020766.3:c.1549G>A
NP_001098713.1:p.Ala517Thr
NP_001171809.1:p.Ala517Thr
NP_065817.2:p.Ala517Thr
LRG_843t1:c.1549G>A
LRG_843:g.8225G>A
LRG_843p1:p.Ala517Thr
NC_000023.10:g.99662047C>T
NC_000023.10:g.99662047C>T
NM_001184880.1:c.1549G>A
p.Ala517Thr

Protein change:

A517T

Links:

dbSNP: rs778072039

NCBI 1000 Genomes Browser:

rs778072039

Molecular consequence:

NM_001105243.2:c.1549G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001184880.2:c.1549G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020766.3:c.1549G>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

Recent activity

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Protein with RING/U-box and TRAF-like domain [Arabidopsis thaliana]
Protein with RING/U-box and TRAF-like domain [Arabidopsis thaliana]
gi|15241972|ref|NP_201086.1|

Protein
Photobacterium leiognathi strain lnuch.21.1 lux-rib copy 2 operon, partial seque...
Photobacterium leiognathi strain lnuch.21.1 lux-rib copy 2 operon, partial sequence
gi|154124935|gb|EF536336.1|

Nucleotide
Homo sapiens collagen triple helix repeat containing 1 (CTHRC1), RefSeqGene on c...
Homo sapiens collagen triple helix repeat containing 1 (CTHRC1), RefSeqGene on chromosome 8
gi|371120669|ref|NG_031985.1|

Nucleotide
Homo sapiens cBGL1 mRNA for cytosolic beta-glucosidase-like protein-1, complete ...
Homo sapiens cBGL1 mRNA for cytosolic beta-glucosidase-like protein-1, complete cds
gi|11559217|dbj|AB017913.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001245183	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 14, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002107571	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 22, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32105270, 36011376, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001245183

Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 14, 2020)

unknown

clinical testing

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

SCV002107571

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 22, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

[Clinical and genetic characteristics of epilepsy caused by mutations in the PCDH19 gene (OMIM: 300088)].

Dadali EL, Mishina IA, Borovikov AO, Sharkov AA, Kanivets IV.

Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(1):55-61. doi: 10.17116/jnevro202012001155. Russian.

PubMed [citation]

PMID:: 32105270

See all PubMed Citations (4)

Details of each submission

From Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics, SCV001245183.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002107571.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 517 of the PCDH19 protein (p.Ala517Thr). This variant is present in population databases (rs778072039, gnomAD 0.002%). This missense change has been observed in individual(s) with PCDH19-related conditions (PMID: 32105270, 36011376). ClinVar contains an entry for this variant (Variation ID: 870165). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCDH19 protein function. 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.

#	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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