16-29813694-GC-GCC
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000358758.12(PRRT2):c.649dup(p.Arg217ProfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000664 in 1,502,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A214A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00072 ( 0 hom. )
Consequence
PRRT2
ENST00000358758.12 frameshift
ENST00000358758.12 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-G-GC is Pathogenic according to our data. Variant chr16-29813694-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PRRT2 | NM_145239.3 | c.649dup | p.Arg217ProfsTer8 | frameshift_variant | 2/4 | ENST00000358758.12 | NP_660282.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PRRT2 | ENST00000358758.12 | c.649dup | p.Arg217ProfsTer8 | frameshift_variant | 2/4 | 1 | NM_145239.3 | ENSP00000351608 | P1 | |
| MVP-DT | ENST00000569039.5 | n.246-3522_246-3521insG | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes 0.000147 AC: 22AN: 149498Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.000721 AC: 975AN: 1352792Hom.: 0 Cov.: 33 AF XY: 0.000694 AC XY: 466AN XY: 671036
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GnomAD4 genome 0.000147 AC: 22AN: 149600Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 10AN XY: 73018
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:70Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Episodic kinesigenic dyskinesia 1 Pathogenic:14Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift variant c.649dupp.Arg217ProfsTer8 in PRRT2 gene has been reported previously in heterozygous state in individuals affected with benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia Wang Y, et al., 2017, Zheng W, et al., 2016. Experimental studies indicate that this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014. The variant is reported with 0.3% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/Pathogenic multiple submissions. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2023 | Variant summary: PRRT2 c.649dupC (p.Arg217ProfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0037 in 135540 control chromosomes, however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.649dupC has been reported in the literature in multiple individuals affected with PRRT2-related conditions (e.g., Ji_2021). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33661484, 25457817). 39 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Mar 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2012 | - - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | May 01, 2016 | Our laboratory reported two molecular diagnoses in KCNQ2 (NM_172108.4, c.2332delC) and PRRT2 (NM_145239.2, c.649dup) in an individual with Ohtahara syndrome, severe developmental delay, seizure disorder, structural brain anomalies and eye anomalies, severe hypotonia, bilateral hearing loss, and dysmorphic features. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Jun 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.649dup;p.(Arg217Profs*8) is a null frameshift variant (NMD) in the PRRT2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65758; PMID: 22101681; 22870186; 22877996; 25667652) - PS4 and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 21, 2024 | Criteria applied: PVS1,PS4,PS3_SUP - |
Infantile convulsions and choreoathetosis Pathogenic:14Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Oct 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Nov 13, 2019 | ACMG codes: PVS1, PM1, PP1, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Aug 11, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 30, 2022 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PM6 moderated, PP1 strong, BS1 strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Sep 06, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Nov 17, 2021 | This variant is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene. The variant has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members [PMID: 22101681, 22845787, 22243967, 23182655, 25522171, 26598493, 29334453]. It has also been reported to have reduced penetrance and variable expression between and within families. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID: 25457817]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 22, 2023 | The observed frameshift c.649dupp.Arg217ProfsTer8 variant in PRRT2 gene has been reported previously in heterozygous state in multiple individuals affected with infantile seizures and/or paroxysmal kinesigenic dyskinesia PKD Zheng W, et al., 2016; Sangu N, et al., 2015; Chen GH., 2015; Steinlein et al., 2012. This variant has been observed to segregate with disease in related individuals. Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein Wu L, et al., 2014. This variant is present with an allele frequency of 0.4% in the gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic multiple submissons. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in PRRT2 are known to be disease causing Méneret A, et al., 2012. For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 23, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM1,PP5. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 21, 2022 | PVS1, PS3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 01, 2024 | Criteria applied: PVS1,PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Heterozygous Frameshift variant c.640_641insC in Exon 2 of the PRRT2 gene that results in the amino acid substitution p.Arg217fs*8 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (Variant ID: 65758). This variant has been identified in patients with infantile choreoathetosis and paroxysmal kinesigenic dyskinesia (Chen WJ et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Seizures, benign familial infantile, 2 Pathogenic:12Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed frameshift c.649dup(p.Arg217ProfsTer8) variant in PRRT2 gene has been reported previously in heterozygous state in individual(s) affected with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (Steinlein et al., 2012; Chen GH., 2015). This variant is reported with the allele frequency of 0.4% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. This variant causes a frameshift starting with codon Arginine 217, changes this amino acid to Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (Méneret et al., 2012). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of [0.003103. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000065758.42, PS4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | research | Pediatrics, Sichuan Provincial Hospital For Women And Children | Feb 16, 2023 | The proband, a male, 9 months old, There was no obvious cause before the onset of convulsion, the form of Generalized tonic-clonic seizures (GTCS), which occurred about 1-2 minutes after spontaneous stop.His mother and grandfather had the same seizure up to the age of six years old, after which they healed - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2012 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Jun 21, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | Jan 01, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 05, 2020 | The inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is the duplication of a single nucleotide, resulting in the frameshift and premature termination of the protein approximately 8 amino acids downstream (coding exon 2/4). This variant is found in 21 heterozygous individuals in gnomAD(v3.0), with an allele frequency of 1.49e-4. This variant is reported in ClinVar as Pathogenic (VarID:65758), and is the most common pathogenic PRRT2 variant identified in affected individuals [PMID:29334453; PMID:26598493; PMID:24370076]. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID:25457817]. Given this, the inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is reported as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 27, 2022 | Criteria applied: PVS1,PS3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Jun 07, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
not provided Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2020 | Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014); 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; Recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene; This variant is associated with the following publications: (PMID: 25522171, 23180180, 25502464, 23535490, 22877996, 22782515, 24661410, 22744660, 24370076, 27959697, 30182498, 30034362, 29250726, 31785815, 31901402, 31302675, 29655203, 26876767, 22101681, 25595153, 22243967, 23768507, 24074546, 22845787, 23771590, 23182655, 23126439, 24609974, 23532549, 22870186, 22623405, 27920401, 25915028, 27123484, 27172900, 28553402, 28097321, 28566192, 28525812, 29215089, 29778030, 29852413, 28018471, 29285950, 29302074, 30501978, 29132464, 30392205, 30125676, 30847922, 30814447, 31780880, 31737037, 31154286, 31722684, 32002278, 31216405, 32246320, 33126500, 34489640, 34298454, 32651081, 33391346, 33327426, 32613771, 33043084, 33258288, 32964447, 25667652, 25457817, 32860008, 33726816, 32237035) - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 06, 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 more than 4,000 samples and varying ethnicities, which is consistent with the pathogenicity of this variant (PMID: 22243967, 22870186, 22875091, 23077024, 23077026, 22399141, 22209761, 22101681, 22131361, 25522171). 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: 23077026, 22782515, 23126439, 22120146, 22623405, 23077017, 23182655, 23771590, 24370076, 25502464). This variant appears to occur de novo in multiple individuals with various PRRT2-related disorders (PMID: 23077026, 22399141). - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 04, 2023 | PVS1, PS3, PS4, PP1, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 29, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 23, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | PRRT2: PVS1, PP1:Strong, PS2, PS4:Moderate - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
PRRT2-related disorder Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 15, 2022 | PVS1, PS4, PP1 - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | The PRRT2 c.649dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Profs*8). This variant has previously been reported to be causative for a broad range of autosomal dominant PRRT2-related phenotypes such as paroxysmal kinesigenic dyskinesia, familial hemiplegic migraine, benign familial infantile epilepsy (BFIE), and paroxysmal torticollis (Chen et al. 2011. PubMed ID: 22101681; Li et al. 2013. PubMed ID: 23535490; Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493; Zhao et al. 2018. PubMed ID: 29285950). In addition to variable expressivity, reduced penetrance is also documented for this gene (Ebrahimi-Fakhari et al. 1993. PubMed ID: 29334453). The c.649dup is the most common pathogenic variant reported in the PRRT2 gene. Note that allele frequency estimates at this position in the gnomAD public population database may be inaccurate. In summary, we classify this variant as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant is a recurrent cause of benign familial infantile epilepsy, infantile convulsions and choreoathetosis, and paroxysmal kinesigenic dyskinesia (PMID: 23299620, 22101681, 22870186, 22877996, 25667652). The c.649dup (p.Arg217ProfsTer8) variant is present in the gnomAD population database at a frequency of 0.3% (514/165666); however, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, the c.649dup (p.Arg217ProfsTer8) variant is classified as Pathogenic. - |
Seizure Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 05, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Mar 05, 2024 | - - |
Seizures, benign familial infantile, 2;C1865926:Infantile convulsions and choreoathetosis;C4552000:Episodic kinesigenic dyskinesia 1 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PS4+PP1_Strong+PM2_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jul 23, 2018 | PRRT2 NM_145239.2 exon 2 p.Arg217Profs*8 (c.649dupC): This variant has been well reported in the literature (including an entry in GeneReviews) and has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members (Chen 2011 PMID:22101681, Dale 2012 PMID:22845787, Heron 2012 PMID:22243967, Castiglioni 2013 PMID:23182655, He 2014 PMID:25522171, Ebrahimi-Fakhari 2015 PMID:26598493, Ebrahimi-Fakhari 2018 PMID:29334453). In addition, a review article suggests that this variant may account for 78.5% of the reported cases in the literature (Ebrahimi-Fakhari 2015 PMID:26598493). This variant is present in 8/29718 alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772994486). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:65758). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an addition of 1 nucleotide within a string of cytosines at position 649 and creates a premature stop codon 8 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Ebrahimi-Fakhari 2015 PMID:26598493). In summary, this variant is classified as pathogenic . - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 18, 2022 | - - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2023 | The c.649dupC (p.R217Pfs*8) alteration, located in exon 2 (coding exon 1) of the PRRT2 gene, results from a duplication of C at position 649, causing a translational frameshift with a predicted alternate stop codon after 8 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, the c.649dupC allele has an overall frequency of 0.31% (514/165666) total alleles studied. The highest observed frequency was 0.47% (22/4682) of Ashkenazi Jewish alleles. The PRRT2 c.649dupC (p.R217Pfs*8) alteration is the most common pathogenic variant in PRRT2 and can be identified in approximately 80% of affected individuals (Ebrahimi-Fakhari, 2015). This alteration has been identified in individuals and families with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, or a combination of these presentations (Chen, 2011; Heron, 2012; Pelzer, 2014; Ebrahimi-Fakhari, 2015). Functional analysis demonstrated that the PRRT2 c.649dupC (p.R217Pfs*8) alteration results in an mRNA transcript that undergoes nonsense mediated decay (Wu, 2014). Any truncated mRNA transcript that is translated has been shown to mislocalize and is found in the cytoplasm rather than the plasma membrane (Chen, 2011). Other studies have found no detectable protein associated with the c.649dupC (p.R217Pfs*8) alteration (Li, 2015). Functional studies have also shown that the c.649dupC (p.R217Pfs*8) alteration results in a protein that is unable to interact with components of the SNARE complex or glutamate receptors (Li, 2015). Based on the available evidence, this alteration is classified as pathogenic. - |
Self-limited familial infantile epilepsy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, 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 familial infantile convulsions with paroxysmal choreoathetosis (MIM#602066), episodic kinesigenic dyskinesia 1 (MIM#128200), benign familial infantile seizures 2 (MIM#605751) and self-limited familial infantile epilepsy (MONDO#0100024). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for paroxysmal kinesigenic dyskinesia (PMID: 29334453). (I) 0115 - Variants in this gene are known to have variable expressivity. Variation in phenotype has been reported within and between families with the same pathogenic variant (PMID: 29334453). (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 (v2) >=0.001 and <0.01 for a dominant condition (514 heterozygotes, 0 homozygotes; variant did not pass quality filter). (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, PMIDs: 22101681, 26561923, 25502464). (SP) 0901 - This variant has strong evidence for segregation with disease (PMIDs: 22101681, 25502464). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
PRRT2-Associated Paroxysmal Movement Disorders Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 26, 2021 | The PRRT2 c.649dupC (p.Arg217ProfsTer8) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. Across a selection of the available literature, the p.Arg217ProfsTer8 variant has been identified in approximately 78% of all 1444 individuals with published PRRT2 variants (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Lee et al. 2012; Becker et al. 2013; Ebrahimi-Fakhari et al. 2015). The phenotype of affected individuals includes paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions and choreoathetosis. The p.Arg217ProfsTer8 variant was found to segregate with disease in many familial cases with high penetrance, although incomplete penetrance in several families has been described (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Becker et al. 2013). The p.Arg217ProfsTer8 variant is reported at a frequency of 0.0001727 in the African/African-American population of the Genome Aggregation Database. PRRT2 is a transmembrane protein, and the p.Arg217ProfsTer8 variant is expected to disrupt the transmembrane domain (Chen et al. 2011). Functional studies demonstrated absence of this truncated protein in transfected cell lines and cultured hippocampal neurons (Lee et al. 2012). Co-transfection of p.Arg217ProfsTer8 with wild-type PRRT2 demonstrated normal expression of wild-type PRRT2 and low/undetectable expression of truncated PRRT2, suggesting haploinsufficiency as the disease mechanism (Lee et al. 2012). Based on the collective evidence and application of ACMG criteria, the variant is classified as pathogenic for PRRT2-associated paroxysmal movement disorders. - |
Episodic kinesigenic dyskinesia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg217Profs*8) 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 infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (PMID: 22101681, 22870186, 22877996, 23299620, 25667652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65758). For these reasons, this variant has been classified as Pathogenic. - |
Convulsions Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PP1,PS4,PM2 - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Aug 24, 2022 | ACMG categories: PVS1,PS4,PP3,PP5,BS1 - |
PRRT2 insufficiency Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2, PM3; observed in two families - |
Paroxysmal nonkinesigenic dyskinesia 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Jun 17, 2019 | - - |
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