In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with the E2727del variant had slower inactivation and faster recovery in response to a mechanical stimulus, suggesting a gain-of-function effect (Coste et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 24532247, 23487782, 31965297, 30131872, 31230720, 28974772, 30169785, 27743844, 30988732, 28636944, 35906671, 35698866, 34203046, 11146470, 17345626, Ma2022[Preprint], 27535533, 24726473)
ClinVar Genomic variation as it relates to human health
NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)
Variation ID: 235839 Accession: VCV000235839.35
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 18p11.22 18: 10671603-10671605 (GRCh38) [ NCBI UCSC ] 18: 10671600-10671602 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 9, 2016 Oct 20, 2024 Jun 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001378183.1:c.8514AGA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365112.1:p.Glu2840del inframe deletion NM_001378183.1:c.8520_8522del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_022068.2:c.8181_8183del NM_022068.3:c.8181_8183del NM_022068.4:c.8175AGA[2] NP_071351.2:p.Glu2727del inframe deletion NC_000018.10:g.10671603TCT[2] NC_000018.9:g.10671600TCT[2] NG_034005.1:g.482152AGA[2] - Protein change
- E2727del, E2840del
- Other names
- -
- Canonical SPDI
- NC_000018.10:10671602:TCTTCTTCT:TCTTCT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| PIEZO2 | - | - |
GRCh38 GRCh37 |
1046 | 1167 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
- | RCV000224433.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 16, 2014 | RCV000415170.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 28, 2022 | RCV000487334.26 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001007806.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 18, 2024 | RCV004649103.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 16, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Distal arthrogryposis
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492762.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
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Pathogenic
(Oct 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000567782.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with … (more)
In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with the E2727del variant had slower inactivation and faster recovery in response to a mechanical stimulus, suggesting a gain-of-function effect (Coste et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 24532247, 23487782, 31965297, 30131872, 31230720, 28974772, 30169785, 27743844, 30988732, 28636944, 35906671, 35698866, 34203046, 11146470, 17345626, Ma2022[Preprint], 27535533, 24726473) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047494.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type … (more)
The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type 5 (Coste et al., 2013; McMillin et al, 2014). Functional studies demonstrate that the c.8181_8183delAGA variant is associated with increased channel activity in response to repetitive mechanical signals (Coste et al., 2013).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu2840del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Glu2840del causes deletion of amino acid Glutamic Acid at position 2840. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Prominent forehead (present) , Downslanted palpebral fissures (present) , Abnormality of the eye (present) , Disproportionate short stature (present) , Relatively short spine (present) , … (more)
Prominent forehead (present) , Downslanted palpebral fissures (present) , Abnormality of the eye (present) , Disproportionate short stature (present) , Relatively short spine (present) , Camptodactyly (present) , Syndactyly (present) , Flexion contracture (present) , Osteopenia (present) , Brachydactyly (present) (less)
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Pathogenic
(Jun 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005149922.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This … (more)
The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This results in the deletion of a glutamic acid residue at codon p.2727. for autosomal dominant PIEZO2-related distal arthrogryposis; however, its clinical significance for autosomal recessive PIEZO2-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant PIEZO2-related distal arthrogryposis. It has also been shown to segregate with disease in affected families (Coste, 2013; McMillin, 2014). This amino acid position is highly conserved in available vertebrate species. In an electrophysiological study, this variant showed a functionally abnormal result (Coste, 2013). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
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Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199010.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
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Pathogenic
(Dec 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248303.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jun 04, 2014)
|
no assertion criteria provided
Method: research
|
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
Affected status: yes
Allele origin:
de novo
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000281713.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
|
|
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Pathogenic
(May 01, 2014)
|
no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS, DISTAL, TYPE 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000114918.5
First in ClinVar: Jan 23, 2014 Last updated: Sep 14, 2018 |
Comment on evidence:
In a woman with generalized arthrogryposis associated with ptosis and ophthalmoplegia as well as restrictive lung disease (DA5; 108145), Coste et al. (2013) identified heterozygosity … (more)
In a woman with generalized arthrogryposis associated with ptosis and ophthalmoplegia as well as restrictive lung disease (DA5; 108145), Coste et al. (2013) identified heterozygosity for a 3-bp deletion (c.8179_8181del) in the PIEZO2 gene, resulting in the in-frame deletion of a single amino acid (glu2727del) within a highly conserved domain of unknown function. Functional studies in transfected cells demonstrated that the 3-bp deletion causes slowing of inactivation of PIEZO2-dependent mechanically activated currents, as well as significantly faster recovery from inactivation compared to wildtype. In affected individuals from 10 families with DA5, including the families originally reported by Pallotta et al. (2000) and Williams et al. (2007), McMillin et al. (2014) identified heterozygosity for the Glu2727del mutation in the PIEZO2 gene. In 1 family, the proband's unaffected father was found to be mosaic for the deletion, which was detected at a low level in peripheral blood (11%), buccal cells (10%), and saliva (12%). (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Gordon syndrome
This variant was identified in an
(more...)
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001167496.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Number of individuals with the variant: 1
Family history: yes
|
Comment:
Comment:
The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type 5 (Coste et al., 2013; McMillin et al, 2014). Functional studies demonstrate that the c.8181_8183delAGA variant is associated with increased channel activity in response to repetitive mechanical signals (Coste et al., 2013).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu2840del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Glu2840del causes deletion of amino acid Glutamic Acid at position 2840. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This results in the deletion of a glutamic acid residue at codon p.2727. for autosomal dominant PIEZO2-related distal arthrogryposis; however, its clinical significance for autosomal recessive PIEZO2-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant PIEZO2-related distal arthrogryposis. It has also been shown to segregate with disease in affected families (Coste, 2013; McMillin, 2014). This amino acid position is highly conserved in available vertebrate species. In an electrophysiological study, this variant showed a functionally abnormal result (Coste, 2013). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment on condition
This variant was identified in an individual with arthrogryposis
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. |
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with the E2727del variant had slower inactivation and faster recovery in response to a mechanical stimulus, suggesting a gain-of-function effect (Coste et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 24532247, 23487782, 31965297, 30131872, 31230720, 28974772, 30169785, 27743844, 30988732, 28636944, 35906671, 35698866, 34203046, 11146470, 17345626, Ma2022[Preprint], 27535533, 24726473)
Comment:
The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type 5 (Coste et al., 2013; McMillin et al, 2014). Functional studies demonstrate that the c.8181_8183delAGA variant is associated with increased channel activity in response to repetitive mechanical signals (Coste et al., 2013).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu2840del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Glu2840del causes deletion of amino acid Glutamic Acid at position 2840. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This results in the deletion of a glutamic acid residue at codon p.2727. for autosomal dominant PIEZO2-related distal arthrogryposis; however, its clinical significance for autosomal recessive PIEZO2-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant PIEZO2-related distal arthrogryposis. It has also been shown to segregate with disease in affected families (Coste, 2013; McMillin, 2014). This amino acid position is highly conserved in available vertebrate species. In an electrophysiological study, this variant showed a functionally abnormal result (Coste, 2013). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment on condition
This variant was identified in an individual with arthrogryposis
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. | McMillin MJ | American journal of human genetics | 2014 | PMID: 24726473 |
| Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. | Coste B | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23487782 |
| Pulmonary disease is a component of distal arthrogryposis type 5. | Williams MS | American journal of medical genetics. Part A | 2007 | PMID: 17345626 |
| Occurrence of Dandy-Walker anomaly in a familial case of distal arthogryposis type IIB. | Pallotta R | American journal of medical genetics | 2000 | PMID: 11146470 |
Text-mined citations for rs1555621138 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.