chrX-100407903-T-C

Position:

• chrX-100407903-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.695A>G​(p.Asn232Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000884 in 113,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 25)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.02

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant X-100407903-T-C is Pathogenic according to our data. Variant chrX-100407903-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407903-T-C is described in Lovd as [Likely_pathogenic]. Variant chrX-100407903-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.695A>G	p.Asn232Ser	missense_variant	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.695A>G	p.Asn232Ser	missense_variant	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.695A>G	p.Asn232Ser	missense_variant	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.695A>G	p.Asn232Ser	missense_variant	1/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.695A>G	p.Asn232Ser	missense_variant	1/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.695A>G	p.Asn232Ser	missense_variant	1/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes AF: 0.00000884 AC: 1 AN: 113178 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35330

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113178 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 232 of the PCDH19 protein (p.Asn232Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 22267240, 22946748, 23808377, 27527380). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 206321). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 11, 2021	PCDH19 NM_001184880.1 exon 1 p.Asn232Ser (c.695A>G): This variant has been reported in the literature in 6 affected individuals with epilepsy, including 3 individuals further characterized with Dravet syndrome (Depienne 2012 PMID:22267240, Marini 2012 PMID:22946748, Gaily 2013 PMID:23808377, Breuillard 2016 PMID:27179713, Liu 2017 PMID:27527380, Smith 2018 PMID:29377098). The variant was reported to be de novo in 4 of these 6 individuals (Marini 2012 PMID:22946748, Gaily 2013 PMID:23808377, Liu 2017 PMID:27527380, Smith 2018 PMID:29377098). This variant is not present in large control databases, and it is present in ClinVar (Variation ID:206321). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206321). The variant has been previously reported as de novo in a similarly affected individual (PMID: 22946748). Different missense changes at the same codon (p.Asn232Ile, p.Asn232Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000159561, VCV000206322, VCV001068161). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2019

The p.N232S pathogenic mutation (also known as c.695A>G), located in coding exon 1 of the PCDH19 gene, results from an A to G substitution at nucleotide position 695. The asparagine at codon 232 is replaced by serine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals, as de novo and inherited, in the literature with various seizure types as well as in individuals with clinical diagnoses of PCDH19 related epilepsy and Dravet syndrome (Liu A et al. Clin. Genet., 2017 Jan;91:54-62; Smith L et al. Epilepsia, 2018 Mar;59:679-689; Marini C et al. Epilepsia. 2012;53(12):2111-9; Gaily E et al. Epilepsia. 2013;54(9):1577-85; Breuillard D et al. Epilepsy Behav, 2016 Jul;60:75-80l; Chemaly N et al. Epileptic Disord, 2018 Dec;20:457-467). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 22267240, 23808377, 22946748, 27179713, 30451291, 32189863, 34489640, 33262389, 33726816, 35571021, 31440721, 36970538, 36403551, 29377098, 27527380) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.7	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.87
MutPred		0.66		Gain of phosphorylation at N232 (P = 0.0764);Gain of phosphorylation at N232 (P = 0.0764);Gain of phosphorylation at N232 (P = 0.0764);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587784299; hg19: chrX-99662901;