rs587778771
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_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
NM_145239.3 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
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 0.0000134 AC: 2AN: 149480Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00193 AC: 2563AN: 1325610Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 1325AN XY: 657646
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GnomAD4 genome 0.0000134 AC: 2AN: 149580Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 2AN XY: 73010
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:10
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 04, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 22, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 08, 2023 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | PRRT2: PVS1, PP1:Strong, PS4:Moderate, PS3:Supporting - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 20, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2020 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Episodic kinesigenic dyskinesia 1 Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 10, 2012 | - - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 08, 2018 | 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] - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 29, 2024 | - - |
Seizures, benign familial infantile, 2 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 10, 2024 | Criteria applied: PVS1,PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jul 17, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PS4 - |
PRRT2-associated paroxysmal movement disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 20, 2024 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | 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; Méneret, 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
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 12, 2024 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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
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