X-100407891-G-C

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.707C>G(p.Pro236Arg) 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. P236L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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-100407891-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 626145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-100407891-G-C is Pathogenic according to our data. Variant chrX-100407891-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408904.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.707C>G	p.Pro236Arg	missense_variant	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.707C>G	p.Pro236Arg	missense_variant	1/5
PCDH19	NM_020766.3	c.707C>G	p.Pro236Arg	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.707C>G	p.Pro236Arg	missense_variant	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.707C>G	p.Pro236Arg	missense_variant	1/5	1		P5
PCDH19	ENST00000420881.6	c.707C>G	p.Pro236Arg	missense_variant	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2016

The P236R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P236R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Two different missense variants in the same codon (P236S, P236L) as well as missense variants in nearby residues (N232S, N234S) have been reported in the Human Gene Mutation Database in association with PCDH19-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, targeted parental test results indicate the P236R variant is apparently de novo in this individual. Therefore, we now interpret P236R as a likely pathogenic variant; however, the possibility that it is benign cannot be excluded. -

Developmental and epileptic encephalopathy, 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro236 amino acid residue in PCDH19. Other variant(s) that disrupt this residue have been observed in individuals with PCDH19-related conditions (PMID: 21480887, 26993267), which suggests that this may be a clinically significant amino acid residue. 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: 408904). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 31487502; Invitae). 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 arginine, which is basic and polar, at codon 236 of the PCDH19 protein (p.Pro236Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	30
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		0.77		Loss of glycosylation at S241 (P = 0.0465);Loss of glycosylation at S241 (P = 0.0465);Loss of glycosylation at S241 (P = 0.0465);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.99

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: rs1060502176; hg19: chrX-99662889;