ClinVar Genomic variation as it relates to human health
NM_020631.6(PLEKHG5):c.1705G>A (p.Asp569Asn)
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_020631.6(PLEKHG5):c.1705G>A (p.Asp569Asn)
Variation ID: 378377 Accession: VCV000378377.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.31 1: 6470331 (GRCh38) [ NCBI UCSC ] 1: 6530391 (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 Mar 8, 2017 May 1, 2024 Jun 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020631.6:c.1705G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065682.2:p.Asp569Asn missense NM_001042663.3:c.1816G>A NP_001036128.2:p.Asp606Asn missense NM_001042664.2:c.1705G>A NP_001036129.1:p.Asp569Asn missense NM_001042665.2:c.1705G>A NP_001036130.1:p.Asp569Asn missense NM_001265592.2:c.1816G>A NP_001252521.2:p.Asp606Asn missense NM_001265593.2:c.1912G>A NP_001252522.1:p.Asp638Asn missense NM_001265594.3:c.1705G>A NP_001252523.1:p.Asp569Asn missense NM_020631.5:c.1705G>A NM_198681.4:c.1705G>A NP_941374.3:p.Asp569Asn missense NC_000001.11:g.6470331C>T NC_000001.10:g.6530391C>T NG_007978.1:g.54679G>A NG_029910.1:g.865G>A LRG_262:g.54679G>A LRG_262t1:c.1705G>A LRG_262p1:p.Asp569Asn - Protein change
- D569N, D638N, D606N
- Other names
- p.Asp569Asn
- Canonical SPDI
- NC_000001.11:6470330: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00034
The Genome Aggregation Database (gnomAD) 0.00034
Trans-Omics for Precision Medicine (TOPMed) 0.00036
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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PLEKHG5 | - | - |
GRCh38 GRCh37 |
1318 | 1427 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 5, 2023 | RCV000438420.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV000525392.16 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2022 | RCV001099856.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 8, 2022 | RCV002411299.9 |
Submissions - Germline
Classification
Help
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
Help
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
Help
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
Help
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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Uncertain significance
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000514180.6
First in ClinVar: Mar 08, 2017 Last updated: Apr 01, 2023 |
Comment:
Reported previously as a variant of uncertain significance in an individual with peripheral neuropathy; however, additional information was not provided (Antoniadi et al., 2015); In … (more)
Reported previously as a variant of uncertain significance in an individual with peripheral neuropathy; however, additional information was not provided (Antoniadi et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26392352) (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neuronopathy, distal hereditary motor, autosomal recessive 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001256345.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Apr 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473095.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The PLEKHG5 c.1705G>A; p.Asp569Asn variant (rs200641225) is reported in the literature in an individual affected with inherited peripheral neuopathy (Antoniadi 2015). This variant is reported … (more)
The PLEKHG5 c.1705G>A; p.Asp569Asn variant (rs200641225) is reported in the literature in an individual affected with inherited peripheral neuopathy (Antoniadi 2015). This variant is reported in ClinVar (Variation ID: 378377), and is found in the general population with an overall allele frequency of 0.030% (85/282250 alleles) in the Genome Aggregation Database. The aspartic acid at codon 569 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Asp569Asn variant is uncertain at this time. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. (less)
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Uncertain significance
(Oct 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronopathy, distal hereditary motor, autosomal recessive 4
Charcot-Marie-Tooth disease recessive intermediate C
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000646007.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 569 of the PLEKHG5 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 569 of the PLEKHG5 protein (p.Asp569Asn). This variant is present in population databases (rs200641225, gnomAD 0.06%). This missense change has been observed in individual(s) with inherited peripheral neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 378377). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronopathy, distal hereditary motor, autosomal recessive 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835558.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Uncertain significance
(Jun 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227734.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4
Number of individuals with the variant: 2
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Uncertain significance
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002715808.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D569N variant (also known as c.1705G>A), located in coding exon 15 of the PLEKHG5 gene, results from a G to A substitution at nucleotide … (more)
The p.D569N variant (also known as c.1705G>A), located in coding exon 15 of the PLEKHG5 gene, results from a G to A substitution at nucleotide position 1705. The aspartic acid at codon 569 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been seen in an individual with features of Charcot-Marie-Tooth disease type 2 (Antoniadi T et al. BMC Med. Genet., 2015 Sep;16:84). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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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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Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. | Antoniadi T | BMC medical genetics | 2015 | PMID: 26392352 |
Text-mined citations for rs200641225 ...
HelpRecord last updated Jun 02, 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.