NM_145239.3(PRRT2):c.649dup (p.Arg217fs) AND Infantile convulsions and choreoathetosis
- Germline classification:
- Pathogenic (13 submissions)
- Last evaluated:
- Dec 30, 2022
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000153783.35
Allele description [Variation Report for NM_145239.3(PRRT2):c.649dup (p.Arg217fs)]
NM_145239.3(PRRT2):c.649dup (p.Arg217fs)
- Genes:
- MVP-DT:MVP divergent transcript [Gene - HGNC]
PRRT2:proline rich transmembrane protein 2 [Gene - OMIM - HGNC] - Variant type:
- Duplication
- Cytogenetic location:
- 16p11.2
- Genomic location:
- Preferred name:
- NM_145239.3(PRRT2):c.649dup (p.Arg217fs)
- HGVS:
- NC_000016.10:g.29813703dup
- NG_032039.1:g.6616dup
- NM_001256442.2:c.649dup
- NM_001256443.2:c.649dup
- NM_145239.3:c.649dupMANE SELECT
- NP_001243371.1:p.Arg217fs
- NP_001243372.1:p.Arg217fs
- NP_660282.2:p.Arg217fs
- NC_000016.9:g.29825015_29825016insC
- NC_000016.9:g.29825024dup
- NM_001256442.1:c.649dup
- NM_001256442.1:c.649dupC
- NM_001256442.2:c.649dup
- NM_001256443.1:c.649dupC
- NM_145239.2:c.649_650insC
- NM_145239.2:c.649dupC
- NM_145239.3:c.640_641insCMANE SELECT
- NM_145239.3:c.649dupCMANE SELECT
- p.Arg217Profs*8
- p.Arg217ProfsX8
- p.R217PfsX8
- NP_660282.2:p.Arg217Profs*8
This HGVS expression did not pass validation- Nucleotide change:
- 649_650insC
- Protein change:
- R217fs
- Links:
- OMIM: 614386.0001
- Molecular consequence:
- NM_001256442.2:c.649dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_001256443.2:c.649dup - frameshift variant - [Sequence Ontology: SO:0001589]
- NM_145239.3:c.649dup - frameshift variant - [Sequence Ontology: SO:0001589]
- Observations:
- 3
Condition(s)
- Name:
- Infantile convulsions and choreoathetosis (ICCA)
- Synonyms:
- Infantile convulsions and paroxysmal choreoathetosis, familial; Convulsions, infantile, with paroxysmal choreoathetosis, familial; PAROXYSMAL KINESIGENIC DYSKINESIA WITH INFANTILE CONVULSIONS
- Identifiers:
- MONDO: MONDO:0011178; MedGen: C1865926; Orphanet: 31709; OMIM: 602066
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000045456 | OMIM | no assertion criteria provided | Pathogenic (Oct 1, 2012) | germline | literature only | |
SCV000747727 | GeneReviews | no classification provided | not provided | germline | literature only | |
SCV001167610 | Genomic Medicine Lab, University of California San Francisco - CSER | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Sep 6, 2018) | maternal | clinical testing | |
SCV001192520 | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 13, 2019) | unknown | research | |
SCV001244945 | Génétique des Maladies du Développement, Hospices Civils de Lyon | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | maternal | clinical testing | |
SCV001368515 | Centre for Mendelian Genomics, University Medical Centre Ljubljana | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 23, 2020) | unknown | clinical testing | |
SCV002029206 | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | no assertion criteria provided | Pathogenic (Oct 25, 2021) | germline | clinical testing | |
SCV002059398 | Centogene AG - the Rare Disease Company | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Aug 11, 2021) | germline | clinical testing | |
SCV002577560 | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 21, 2022) | germline | clinical testing | |
SCV003807085 | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 30, 2022) | germline | clinical testing | |
SCV003842254 | Lifecell International Pvt. Ltd | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
SCV004042676 | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | paternal | clinical testing | |
SCV004101501 | Neuberg Centre For Genomic Medicine, NCGM | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | maternal | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | literature only |
not provided | paternal | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
not provided | unknown | yes | 1 | not provided | not provided | 1 | not provided | clinical testing, research |
Asian | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gécz J, Thomas PQ, Mulley JC, Berkovic SF, et al.
Am J Hum Genet. 2012 Jan 13;90(1):152-60. doi: 10.1016/j.ajhg.2011.12.003.
- PMID:
- 22243967
- PMCID:
- PMC3257886
PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population.
Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, Lagroua I, Bouteiller D, Mignot C, Doummar D, Anheim M, Tranchant C, Burbaud P, Jedynak CP, Gras D, Steschenko D, Devos D, Billette de Villemeur T, Vidailhet M, Brice A, Roze E.
Neurology. 2012 Jul 10;79(2):170-4. doi: 10.1212/WNL.0b013e31825f06c3. Epub 2012 Jun 27.
- PMID:
- 22744660
Details of each submission
From OMIM, SCV000045456.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (6) |
Description
In affected members of 6 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1 (EKD1; 128200), Chen et al. (2011) identified a heterozygous 1-bp duplication (649dupC) in exon 2 of the PRRT2 gene in the proline-rich domain, resulting in a frameshift and introduction of a stop codon 7 amino acids downstream of the insertion (Arg217ProfsTer8). The mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The mutation completely segregated with the phenotype in each family and was not found in unaffected family members. The mutation was not found in 1,000 Han Chinese controls. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm. A 189-kb common haplotype flanking the mutation was found in 3 of the families, a second different haplotype was found in 2 other families, and a third haplotype was found in the third family. Clinical features of the proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution.
Using a combination of exome sequencing and linkage analysis in a large Han Chinese family with EKD1, Wang et al. (2011) independently and simultaneously identified a heterozygous 649dupC mutation in the PRRT2 gene that completely segregated with the phenotype. The mutation was predicted to result in a truncated protein containing only 223 amino acids and lacking the transmembrane segment. Two patients in the family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066). Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation. The mutation was not found in 500 controls. There was some phenotypic variability: the first family had dystonia, choreoathetosis or athetosis, the second family had predominant dystonia of the upper limbs, whereas the third had predominant dystonia of the lower limbs.
In affected members of 3 unrelated families with familial infantile convulsions with paroxysmal choreoathetosis, Heron et al. (2012) identified a heterozygous 649dupC mutation. This heterozygous mutation was also found in 12 unrelated families with benign familial infantile seizures-2 (BFIS2; 605751). Overall, the 649dupC mutation was found in 15 (79%) of the 19 families with ICCA or BFIS2 studied. There was no evidence of a common haplotype among these families. The PRRT2 649dupC mutation clearly occurs at a mutation hotspot, and occurs in a homopolymer of 9 C bases adjacent to 4 G bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication.
Meneret et al. (2012) found that the 649dupC mutation was the most common mutation in a cohort of patients of European descent with EKD1/ICCA. The mutation was present in 17 of 22 patients with PRRT2 mutations. Several unaffected family members also carried the mutation, indicating incomplete penetrance. There were at least 5 different haplotypes with the mutation, and it was found to occur de novo in 2 patients, indicating that it is a mutation hotspot.
Schubert et al. (2012) identified a heterozygous 649dupC mutation in the PRRT2 gene in 39 of 49 families with BFIS2 and in 1 patient with sporadic occurrence of the disorder (77% of index cases). The patients were of German, Italian, Japanese, and Turkish origin. The 649dupC mutation, which occurs in an unstable DNA sequence of 9 cytosines, arose independently in families of different origin. Some unaffected family members also carried the mutation, indicating incomplete penetrance.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From GeneReviews, SCV000747727.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (6) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Genomic Medicine Lab, University of California San Francisco - CSER, SCV001167610.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | maternal | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001192520.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | research | PubMed (1) |
Description
ACMG codes: PVS1, PM1, PP1, PP5
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided |
From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001244945.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | maternal | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368515.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM1,PP5.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV002029206.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Centogene AG - the Rare Disease Company, SCV002059398.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV002577560.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
PVS1, PS3, PP5
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807085.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
ACMG classification criteria: PVS1 very strong, PS3 supporting, PM6 moderated, PP1 strong, BS1 strong
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Lifecell International Pvt. Ltd, SCV003842254.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | Asian | 1 | not provided | not provided | clinical testing | PubMed (2) |
Description
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.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided |
From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004042676.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | paternal | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided |
From Neuberg Centre For Genomic Medicine, NCGM, SCV004101501.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
The frameshift c.649dup (p.Arg217ProfsTer8) variant has been reported previously in heterozygous state in patients affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Swoboda KJ. et. al., 2000; Lee HY et. al., 2012).This position has been reported to be a mutational hotspot (Mao CY et. al., 2014) and as such, this variant is considered one of the most common, recurrent causes of both PKD and benign familial infantile seizures (Steinlein OK et. al., 2012; Becker F et. al., 2013). The p.Arg217ProfsTer8 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This mutation creates a premature translational stop signal (p.Arg217Profs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Apr 15, 2024