rs796052837

Positions:

• chrX-100408100-G-C
• chrX-100408100-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001184880.2(PCDH19):​c.498C>G​(p.Tyr166Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PCDH19 NM_001184880.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.505

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-100408100-G-C is Pathogenic according to our data. Variant chrX-100408100-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 206361.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.498C>G	p.Tyr166Ter	stop_gained	1/6	ENST00000373034.8
PCDH19	NM_001105243.2	c.498C>G	p.Tyr166Ter	stop_gained	1/5
PCDH19	NM_020766.3	c.498C>G	p.Tyr166Ter	stop_gained	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH19	ENST00000373034.8	c.498C>G	p.Tyr166Ter	stop_gained	1/6	1	NM_001184880.2	A1
PCDH19	ENST00000255531.8	c.498C>G	p.Tyr166Ter	stop_gained	1/5	1		P5
PCDH19	ENST00000420881.6	c.498C>G	p.Tyr166Ter	stop_gained	1/5	1		A1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 206361). This premature translational stop signal has been observed in individuals with PCDH19-related conditions (PMID: 29377098, 31618753, 32425876). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr166*) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with early infantile epileptic encephalopathy 9 (MIM#300088). (I) 0110 - This gene is associated with X-linked dominant disease. Heterozygous females are most often affected, however mosaic males have also been reported. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is absent in gnomAD (both v2 and v3); however, a different nucleotide change resulting in the same protein change is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0701 - Other variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. More than a hundred other NMD-predicted variants have previously been reported as pathogenic in patients with early infantile epileptic encephalopathy 9 (MIM#300088) (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in patients with early infantile epileptic encephalopathy 9 (MIM#300088), including a heterozygous female where the variant was inherited from an affected mother, and a mosaic male in whom the variant was shown to be de novo (ClinVar, PMID: 29377098, PMID: 32425876). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2022

Reported previously in a mother and daughter with seizures, developmental delay/learning disability, and/or autism (Smith et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32425876, 31928905, 29377098, 31618753) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.65	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.83
GERP RS		-3.9

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: rs796052837; hg19: chrX-99663098;