NM_001184880.2(PCDH19):c.1639G>C (p.Ala547Pro) AND Developmental and epileptic encephalopathy, 9

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 2, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001218626.10

Allele description [Variation Report for NM_001184880.2(PCDH19):c.1639G>C (p.Ala547Pro)]

NM_001184880.2(PCDH19):c.1639G>C (p.Ala547Pro)

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.1639G>C (p.Ala547Pro)

HGVS:

NC_000023.11:g.100406959C>G
NG_021319.1:g.8315G>C
NM_001105243.2:c.1639G>C
NM_001184880.2:c.1639G>CMANE SELECT
NM_020766.3:c.1639G>C
NP_001098713.1:p.Ala547Pro
NP_001171809.1:p.Ala547Pro
NP_065817.2:p.Ala547Pro
LRG_843t1:c.1639G>C
LRG_843:g.8315G>C
LRG_843p1:p.Ala547Pro
NC_000023.10:g.99661957C>G
NM_001184880.1:c.1639G>C

Protein change:

A547P

Links:

dbSNP: rs1928375454

NCBI 1000 Genomes Browser:

rs1928375454

Molecular consequence:

NM_001105243.2:c.1639G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001184880.2:c.1639G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020766.3:c.1639G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001390514	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002583535	Pediatric Department, Peking University First Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 1, 2022)	de novo	research	PubMed (2) [See all records that cite these PMIDs] 31031587, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001390514

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 2, 2022)

germline

clinical testing

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

SCV002583535

Pediatric Department, Peking University First Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 1, 2022)

de novo

research

PubMed (2)
[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	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.

Xiong J, Chen S, Pang N, Deng X, Yang L, He F, Wu L, Chen C, Yin F, Peng J.

Front Neurosci. 2019;13:349. doi: 10.3389/fnins.2019.00349.

PubMed [citation]

PMID:: 31031587
PMCID:: PMC6470315

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001390514.5

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 947530). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 547 of the PCDH19 protein (p.Ala547Pro).

#	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 Pediatric Department, Peking University First Hospital, SCV002583535.1

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

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

Last Updated: Sep 29, 2024

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