rs201989363

Positions:

• chrX-100406898-G-A
• chrX-100406898-G-C
• chrX-100406898-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.1700C>T​(p.Pro567Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.14

Genes affected

PCDH19 (HGNC:14270): (protocadherin 19) The protein encoded by this gene is a member of the delta-2 protocadherin subclass of the cadherin superfamily. The encoded protein is thought to be a calcium-dependent cell-adhesion protein that is primarily expressed in the brain. Mutations in this gene on human chromosome X are associated with sporadic infantile epileptic encephalopathy and to a female-restricted form of epilepsy (EFMR; also known as PCDH19RE). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-100406898-G-A is Pathogenic according to our data. Variant chrX-100406898-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100406898-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1700C>T	p.Pro567Leu	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1700C>T	p.Pro567Leu	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.1700C>T	p.Pro567Leu	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1700C>T	p.Pro567Leu	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.1700C>T	p.Pro567Leu	missense_variant	1/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.1700C>T	p.Pro567Leu	missense_variant	1/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PCDH19 function (PMID: 34082468). 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 not expected to disrupt PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 449356). This missense change has been observed in individual(s) with PCDH19-related conditions (PMID: 21053371, 30530412). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 567 of the PCDH19 protein (p.Pro567Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2017

The P567L variant in the PCDH19 gene has been reported previously in several females with epilepsy and intellectual disability, including at least one family where the variant was inherited from an asymptomatic mother and at least one family where the variant was apparently de novo (Depienne et al., 2011; Marini et al., 2012; Cappelletti et al., 2015). The P567L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P567L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, but in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P567L as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.80
DEOGEN2	Benign	0.030	.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.085	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.45	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		1.0, 0.069	.;D;B
Vest4		0.65
MutPred		0.42		Loss of catalytic residue at P566 (P = 0.0296);Loss of catalytic residue at P566 (P = 0.0296);Loss of catalytic residue at P566 (P = 0.0296);
MVP		0.88
MPC		0.55
ClinPred		0.50	D
GERP RS		5.8
Varity_R		0.22
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201989363; hg19: chrX-99661896;