rs772837341

chrX-100408005-C-AchrX-100408005-C-GchrX-100408005-C-T

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.593G>T(p.Arg198Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.91

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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-100408006-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1385337.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-100408005-C-A is Pathogenic according to our data. Variant chrX-100408005-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH19	NM_001184880.2	c.593G>T	p.Arg198Leu	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.593G>T	p.Arg198Leu	missense_variant	1/5
PCDH19	NM_020766.3	c.593G>T	p.Arg198Leu	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.593G>T	p.Arg198Leu	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.593G>T	p.Arg198Leu	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.593G>T	p.Arg198Leu	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2017	The R198L variant in the PCDH19 gene has been reported previously in a female with early-onset seizures and autistic features (Higurashi et al., 2013). The R198L variant is not observed in large population cohorts (Lek et al., 2016). The R198L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -

developmental delay with seizures Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 30, 2016

- -

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 19, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 449358). This missense change has been observed in individual(s) with clinical features of PCDH19-related conditions (PMID: 23712037, 29377098). 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 arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 198 of the PCDH19 protein (p.Arg198Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	29
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.4	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.93
MutPred		0.93		Loss of phosphorylation at T200 (P = 0.0635);Loss of phosphorylation at T200 (P = 0.0635);Loss of phosphorylation at T200 (P = 0.0635);
MVP		0.90
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.94

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: rs772837341; hg19: chrX-99663003;