X-100406916-G-A

Variant names:

• chrX-100406916-G-A
• rs796052819
• NM_001184880.2:c.1682C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.1682C>T​(p.Pro561Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P561R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 8 publications found

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]

PCDH19 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 9

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001184880.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-100406916-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206337.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 2.5929 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Dravet syndrome, developmental and epileptic encephalopathy, 9, X-linked complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-100406916-G-A is Pathogenic according to our data. Variant chrX-100406916-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1023566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 5		NP_001098713.1
PCDH19	NM_020766.3	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 6	1	NM_001184880.2	ENSP00000362125.4
PCDH19	ENST00000255531.8	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 5	1		ENSP00000255531.7
PCDH19	ENST00000420881.6	c.1682C>T	p.Pro561Leu	missense_variant	Exon 1 of 5	1		ENSP00000400327.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a female proband with epilepsy, developmental delay, dysmorphic features, and behavioral concerns; the variant was inherited from the asymptomatic mother, with essentially normal X-inactivation studies and no evidence of mosaicism suggesting incomplete penetrance in the mother(PMID: 38891919); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 39017914, 38891919) -

Developmental and epileptic encephalopathy, 9 Pathogenic:1

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 561 of the PCDH19 protein (p.Pro561Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early infantile epileptic encephalopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 1023566). 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 with a positive predictive value of 95%. This variant disrupts the p.Pro561 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 30287595). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H;H
PhyloP100		10
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.2	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.94
MutPred		0.90		Loss of glycosylation at T564 (P = 0.0877);Loss of glycosylation at T564 (P = 0.0877);Loss of glycosylation at T564 (P = 0.0877);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		6.0
PromoterAI		0.0044	Neutral
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs796052819; hg19: chrX-99661914;