rs1555985301

Positions:

• chrX-100407465-G-C

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.1133C>G​(p.Ser378Ter) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PCDH19 NM_001184880.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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.

• 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-100407465-G-C is Pathogenic according to our data. Variant chrX-100407465-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 447916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-100407465-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH19	NM_001184880.2	c.1133C>G	p.Ser378Ter	stop_gained	1/6	ENST00000373034.8	NP_001171809.1
PCDH19	NM_001105243.2	c.1133C>G	p.Ser378Ter	stop_gained	1/5		NP_001098713.1
PCDH19	NM_020766.3	c.1133C>G	p.Ser378Ter	stop_gained	1/5		NP_065817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH19	ENST00000373034.8	c.1133C>G	p.Ser378Ter	stop_gained	1/6	1	NM_001184880.2	ENSP00000362125	A1
PCDH19	ENST00000255531.8	c.1133C>G	p.Ser378Ter	stop_gained	1/5	1		ENSP00000255531	P5
PCDH19	ENST00000420881.6	c.1133C>G	p.Ser378Ter	stop_gained	1/5	1		ENSP00000400327	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2018	The S378X nonsense variant in the PCDH19 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S378X variant is not observed in large population cohorts (Lek et al., 2016). Although this pathogenic variant has not been reported previously to our knowledge, its presence is consistent with the diagnosis of a PCDH19-related disorder in this individual. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2017	- -

Developmental and epileptic encephalopathy, 9 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	Feb 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 447916). This premature translational stop signal has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 30287595). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser378*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.79
GERP RS		6.0

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: rs1555985301; hg19: chrX-99662463;