ClinVar Genomic variation as it relates to human health
NM_015488.5(PNKD):c.20C>T (p.Ala7Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015488.5(PNKD):c.20C>T (p.Ala7Val)
Variation ID: 1893 Accession: VCV000001893.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 218270555 (GRCh38) [ NCBI UCSC ] 2: 219135278 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 23, 2024 May 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015488.5:c.20C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056303.3:p.Ala7Val missense NM_001077399.3:c.20C>T NP_001070867.1:p.Ala7Val missense NC_000002.12:g.218270555C>T NC_000002.11:g.219135278C>T NG_017060.1:g.5164C>T NG_033036.1:g.4616G>A Q8N490:p.Ala7Val - Protein change
- A7V
- Other names
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- Canonical SPDI
- NC_000002.12:218270554:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOC129935594 | - | - | - | GRCh38 | - | 53 |
PNKD | - | - |
GRCh38 GRCh37 |
89 | 630 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2022 | RCV000001970.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 1, 2023 | RCV001050396.6 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Paroxysmal nonkinesigenic dyskinesia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769268.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as pathogenic in multiple individuals with paroxysmal nonkinesigenic dyskinesia (PMID: 15262732, 15496428, 15824259). (P) 0901 - Strong evidence for segregation with disease. The variant has also been shown to segregate with disease in multiple families (PMID: 15262732, 15496428, 15824259). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(May 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paroxysmal nonkinesigenic dyskinesia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001214500.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PNKD function (PMID: 19124534, 21487022). An algorithm developed to … (more)
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PNKD function (PMID: 19124534, 21487022). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1893). This variant is also known as 66C>T. This missense change has been observed in individuals with paroxysmal non-kinesigenic dyskinesia or paroxysmal dystonic choreoathetosis (PMID: 15262732, 15496428, 22967746, 25107857). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 7 of the PNKD protein (p.Ala7Val). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paroxysmal nonkinesigenic dyskinesia 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581457.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PP1_MOD, PP3
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Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Apr 01, 2005)
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no assertion criteria provided
Method: literature only
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PAROXYSMAL NONKINESIGENIC DYSKINESIA 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022128.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 15, 2019 |
Comment on evidence:
In 4 affected members of a family with PNKD1 (118800), Rainier et al. (2004) identified a heterozygous 66C-T transition in exon 1 of the MR1 … (more)
In 4 affected members of a family with PNKD1 (118800), Rainier et al. (2004) identified a heterozygous 66C-T transition in exon 1 of the MR1 gene, resulting in an ala7-to-val (A7V) substitution. The mutation occurs in a conserved N-terminal alpha helix of the protein and was not identified in 105 controls. In affected members of 5 unrelated families with PNKD1, Lee et al. (2004) identified the A7V mutation. The mutation was not present in over 250 unrelated controls. In affected members of a large PNKD1 family of French and Irish origin, Chen et al. (2005) identified the A7V substitution. Haplotype analysis suggested that the mutation arose independently from that found in the family reported by Rainier et al. (2004). (less)
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Likely pathogenic
(Jun 12, 2024)
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no assertion criteria provided
Method: curation
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Paroxysmal nonkinesigenic dyskinesia 1
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891541.2
First in ClinVar: Oct 11, 2015 Last updated: Jun 23, 2024 |
Geographic origin: Middle East
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not provided
(-)
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no classification provided
Method: literature only
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Paroxysmal nonkinesigenic dyskinesia 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000998892.2
First in ClinVar: Nov 15, 2019 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A case of familial paroxysmal nonkinesigenic dyskinesia due to mutation of the PNKD gene in Chinese Mainland. | Liang S | Brain research | 2015 | PMID: 25107857 |
Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family. | Yeh TH | Journal of the neurological sciences | 2012 | PMID: 22967746 |
Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability. | Shen Y | Human molecular genetics | 2011 | PMID: 21487022 |
Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence. | Ghezzi D | Human molecular genetics | 2009 | PMID: 19124534 |
Presence of alanine-to-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia: confirmation in 2 kindreds. | Chen DH | Archives of neurology | 2005 | PMID: 15824259 |
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. | Lee HY | Human molecular genetics | 2004 | PMID: 15496428 |
Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. | Rainier S | Archives of neurology | 2004 | PMID: 15262732 |
Text-mined citations for rs121434512 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.