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	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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). -

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;