NM_145239.3:c.649delC

Variant names:

• chr16-29813694-GC-G
• rs587778771
• NM_145239.3:c.649delC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_145239.3(PRRT2):​c.649delC​(p.Arg217GlufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,475,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: PRRT2 NM_145239.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 0.693

Genes affected

PRRT2 (HGNC:30500): (proline rich transmembrane protein 2) This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages. Mutations in this gene are associated with episodic kinesigenic dyskinesia-1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ENSG00000280893 (HGNC:):

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-29813694-GC-G is Pathogenic according to our data. Variant chr16-29813694-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic]. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic]. Variant chr16-29813694-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRT2	NM_145239.3	c.649delC	p.Arg217GlufsTer12	frameshift_variant	Exon 2 of 4	ENST00000358758.12	NP_660282.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRT2	ENST00000358758.12	c.649delC	p.Arg217GlufsTer12	frameshift_variant	Exon 2 of 4	1	NM_145239.3	ENSP00000351608.7
ENSG00000280893	ENST00000609618.2	n.649delC		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149480 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00193 AC: 2563 AN: 1325610 Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 1325 AN XY: 657646

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.000684

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149580 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 2 AN XY: 73010

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00779 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRRT2: PVS1, PP1:Strong, PS4:Moderate, PS3:Supporting -

Feb 01, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common pathogenic variant that accounts for approximately 4% of all pathogenic variants in the PRRT2 gene (Ebrahimi-Fakhari et al., 2015); Reported previously in unrelated individuals with PRRT2-related disorders (Meneret et al., 2012; Yang et al., 2013; Ebrahimi-Fakhari et al., 2015); Published functional studies in transfected HEK cells demonstrate a damaging effect as this variant results in a protein that fails to target to the cell membrane (Liu et al., 2016); Frameshift 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; This variant is associated with the following publications: (PMID: 25522171, 22870186, 23077016, 26446061, 24755245, 23551744, 25060993, 24609974, 24101679, 22752065, 23165339, 24465263, 25502464, 23363396, 24370076, 25449067, 28906077, 26598493, 29655203, 31487502, 31901402, 31902651, 32369273, 27172900, 34012299, 32651081, 22744660) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population appears higher than would generally be expected for pathogenic variants in this gene, however, the data have failed quality metrics and thus are not useful in evaluating the pathogenicity of this variant (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has not been reported in control populations composed of almost 2,000 samples and varying ethnicities, which is consistent with the pathogenicity of this variant (PMID: 22744660, 22870186, 22870186, 23551744, 24101679, 24370076, 24465263, 24609974, 25060993, 25522171, 26446061, 32651081, 35428900). This variant associates with various PRRT2-related disorders in multiple families, and is also reported to have reduced penetrance and variable expression between and within families (PMID: 24370076, 24755245, 36247910, 24101679, 25060993). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID 37793168) -

May 22, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic kinesigenic dyskinesia 1 Pathogenic:5

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 22744660, 24755245, 25522171, 28906077, 27172900, 24370076, 25449067] -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jul 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Seizures, benign familial infantile, 2 Pathogenic:3

Sep 10, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4 -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frame shift c.649del (p.Arg217GlufsTer12) variant in the PRRT2 gene has been reported previously in multiple individuals with PRRT2-related disorders (Meneret et al., 2012). This variant has been reported to segregate with PRRT2-related conditions in families (Brueckner F et al., 2014). The p.Arg217GlufsTer12 variant is reported with the allele frequency (0.4%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Arg217GlufsTer12. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 17, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 Pathogenic:2

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PS4 -

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PRRT2-associated paroxysmal movement disorder Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, 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 PRRT2-associated paroxysmal movement disorder (MONDO:0100556). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:22744660). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported in a family carrying this variant, clinical findings ranged from febrile convulsions, paroxysmal kinesigenic dyskinesia and benign infantile familial convulsions to a normal clinical picture (PMID: 24755245). (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) 0310 - Variant is present in gnomAD (v4) >=0.001 and <0.01 for a dominant condition (2565 heterozygotes, 0 homozygotes). However, as this variant is in a GC-rich region and it is present in almost exclusively exome samples in gnomAD, this high frequency is likely due to a sequencing artefact. (I) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with PRRT2-related disorders (ClinVar), and has been reported in individuals with a range of PRRT2-related features in the literature (PMID: 31722684, 24755245). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Episodic kinesigenic dyskinesia Pathogenic:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg217Glufs*12) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of PRRT2-related conditions (PMID: 22744660, 23077016, 24370076, 24755245, 25522171). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39752). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Apr 18, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.649delC (p.R217Efs*12) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, consists of a deletion of one nucleotide at position 649, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/149480) total alleles studied. The highest observed frequency was 0.007% (1/15022) of Latino/Admixed American alleles. This alteration was reported in several individuals and families with variable phenotypes within the spectrum of PRRT2-related paroxysmal movement disorders (Riant, 2012; M&eacute;neret, 2012; Yang, 2013; He, 2014; Brueckner, 2014; Zeng, 2018). This alteration is found in about 4% of PRRT2-related benign familial infantile epilepsy cases (Ebrahimi-Fakhari, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

PRRT2-related disorder Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PRRT2 c.649delC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Glufs*12). This variant is among the most frequently reported causes of PRRT2-related epilepsy, accounting for approximately 4% of affected individuals (Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493). This variant has been reported in patients with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with paroxysmal choreoathetosis and febrile seizures (Méneret et al. 2012. PubMed ID: 22744660; Brueckner et al. 2014. PubMed ID: 24755245; He et al. 2014. PubMed ID: 25522171; Yang et al. 2013. PubMed ID: 24370076). This variant is classified as pathogenic. -

Infantile convulsions and choreoathetosis Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.649delC pathogenic variant in the PRRT2 gene has been reported previously in multiple unrelated individuals affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Meneret et al., 2012). This variant has been reported to segregate with PRRT2-related conditions in families (Brueckner et. al., 2014) and has been reported in individuals affected with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, (Meneret et al., 2012; Yang X et. al., 2013). The p.Arg217GlufsTer12 variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Arg217GlufsTer12. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587778771; hg19: chr16-29825015;