rs796052839

chrX-100407579-T-CchrX-100407579-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001184880.2(PCDH19):c.1019A>G(p.Asn340Ser) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N340T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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-100407579-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-100407579-T-C is Pathogenic according to our data. Variant chrX-100407579-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 206364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407579-T-C is described in Lovd as [Pathogenic]. Variant chrX-100407579-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.1019A>G	p.Asn340Ser	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.1019A>G	p.Asn340Ser	missense_variant	1/5
PCDH19	NM_020766.3	c.1019A>G	p.Asn340Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.1019A>G	p.Asn340Ser	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.1019A>G	p.Asn340Ser	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.1019A>G	p.Asn340Ser	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2022	Published functional studies demonstrate a damaging effect, including reduced thermostability and lack of adhesive function (Pederick et al., 2018); 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; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22949144, 21519002, 27787195, 22946748, 22050978, 22848613, 19214208, 21480887, 22267240, 27527380, 27143072, 29377098, 29064093, 29301106, 29892053, 30287595, 30451291, 31302675, 34082468, 33262389, 32005694, 33399642, 23334464, 20713952, 2267240) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified and confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant showed drastically altered cell adhesion properties and abnormal cell type sorting (PMID: 29301106). -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Developmental and epileptic encephalopathy, 9 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense variant c.1019A>G (p.Asn340Ser) in the PCDH19 gene has been has been observed in individual(s) with early onset severe seizures. In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals (Liu A, et al., 2017; van Harssel JJ, et al., 2013). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant showed drastically altered cell adhesion properties and abnormal cell type sorting (Pederick DT, et al., 2018). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic. The amino acid Asn at position 340 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 340 of the PCDH19 protein (p.Asn340Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset severe seizures (PMID: 2267240, 19214208, 20713952, 21480887, 22848613, 22946748, 23334464, 27527380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206364). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 08, 2022	PM1, PM2, PM5, PP2, PP3, PP5 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2017

The p.N340S pathogenic mutation (also known as c.1019A>G), located in coding exon 1 of the PCDH19 gene, results from an A to G substitution at nucleotide position 1019. The asparagine at codon 340 is replaced by serine, an amino acid with highly similar properties. This mutation has been detected as a de novo occurrence (parental testing was performed, but paternity was not confirmed) in four unrelated individuals with intellectual disability and delays as well as a variety of seizure types including: febrile, focal, generalized tonic-clonic, and partial. Three of these four individuals were initially diagnosed with Dravet syndrome (Depienne C, et al. PLoS Genet. 2009; 5(2):e1000381, Specchio N, et al. Epilepsia 2011; 52(7):1251-7, Marini C, et al. Neurology 2010; 75(7):646-53). This mutation was also detected in an additional female proband with epilepsy, intellectual disability and overlapping features of Dravet syndrome (Kwong AK, et al. PLoS ONE 2012; 7(7):e41802). In addition, two cases of somatic and gonadal mosaicism of this mutation have been observed. The first was in a mother with refractory seizure clusters from ages 1-14 years who transmitted the mutation to two daughters with epilepsy and mental retardation limited to females (EFMR) (Dibbens LM, et al. Neurology 2011; 76(17):1514-9). The second was an unaffected mother who transmitted the mutation to her daughter who developed multiple seizure types before age 1 year (Terracciano A, et al. Neurogenetics 2012; 13(4):341-5). In addition, in vitro analysis of the N340S protein showed that the protein may be folded as well as wild type, but not as stable (Cooper SR et al. Elife, 2016 Oct 26;5. pii: e18529). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Medical Genomics-TUH, Thammasat University

Jul 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	26
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.0	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.87
MutPred		0.83		Loss of stability (P = 0.0591);Loss of stability (P = 0.0591);Loss of stability (P = 0.0591);
MVP		0.95
MPC		2.0
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.95

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: rs796052839; hg19: chrX-99662577;