ClinVar Genomic variation as it relates to human health
NM_001142864.4(PIEZO1):c.7367G>A (p.Arg2456His)
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_001142864.4(PIEZO1):c.7367G>A (p.Arg2456His)
Variation ID: 55806 Accession: VCV000055806.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 88715804 (GRCh38) [ NCBI UCSC ] 16: 88782212 (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 Aug 22, 2016 Feb 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001142864.4:c.7367G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001136336.2:p.Arg2456His missense NC_000016.10:g.88715804C>T NC_000016.9:g.88782212C>T NG_042229.1:g.74417G>A LRG_1137:g.74417G>A LRG_1137t1:c.7367G>A LRG_1137p1:p.Arg2456His Q92508:p.Arg2456His - Protein change
- R2456H
- Other names
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- Canonical SPDI
- NC_000016.10:88715803: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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PIEZO1 | - | - |
GRCh38 GRCh37 |
1154 | 1856 |
Conditions - Germline
Condition
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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
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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 (2) |
criteria provided, single submitter
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Jul 20, 2019 | RCV000049232.14 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV001388579.26 |
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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Pathogenic
(Jul 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001523814.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004026674.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Pathogenic
(Feb 28, 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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Revvity Omics, Revvity
Accession: SCV003822863.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 18, 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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Invitae
Accession: SCV001589630.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2456 of the PIEZO1 protein (p.Arg2456His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2456 of the PIEZO1 protein (p.Arg2456His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary xerocytosis (PMID: 22529292, 23581886, 23973043, 24314002). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55806). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIEZO1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIEZO1 function (PMID: 23479567, 23487776, 23695678, 28716860). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 14, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885906.4
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
The PIEZO1 c.7367G>A; p.Arg2456His variant is reported to co-segregate with dehydrated hereditary stomatocytosis in at least 42 individuals from 6 different families (Andolfo 2013, Beneteau … (more)
The PIEZO1 c.7367G>A; p.Arg2456His variant is reported to co-segregate with dehydrated hereditary stomatocytosis in at least 42 individuals from 6 different families (Andolfo 2013, Beneteau 2014, Russo 2018, Sandberg 2014, Shmukler 2014, Zarychanski 2012). In vitro functional analyses demonstrate prolonged cation channel activity leading to reduced osmotic fragility (Albuisson 2013, Andolfo 2013, Bae 2013, Glogowska 2017, Shmukler 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2456 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Albuisson J et al. Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels. Nat Commun. 2013 4:1884. Andolfo I et al. Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood. 2013 121:3925-3935, S3921-3912. Bae C et al. Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1. Proc Natl Acad Sci U S A. 2013 110:E1162-1168. Beneteau C et al. Recurrent mutation in the PIEZO1 gene in two families of hereditary xerocytosis with fetal hydrops. Clin Genet. 2014 85:293-295. Shmukler BE et al. Dehydrated stomatocytic anemia due to the heterozygous mutation R2456H in the mechanosensitive cation channel PIEZO1: a case report. Blood Cells Mol Dis. 2014 52:53-54. Zarychanski R et al. Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. Blood. 2012 120:1908-1915. (less)
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Pathogenic
(Feb 14, 2022)
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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: SCV002098177.2
First in ClinVar: Feb 26, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a reduced threshold for activation and prolonged channel activation, suggesting a gain-of-function effect (Bae et al., 2013; Glogowska et al., 2017); … (more)
Published functional studies demonstrate a reduced threshold for activation and prolonged channel activation, suggesting a gain-of-function effect (Bae et al., 2013; Glogowska et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25561736, 23973043, 23581886, 24314002, 23695678, 23487776, 22529292, 28716860, 21944700, 31624108, 31040790, 23479567, 29673682, 23972832, 31030808, 29797310, 30655378, 29396846, 31737919, 34201899) (less)
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Pathogenic
(May 09, 2013)
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no assertion criteria provided
Method: literature only
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DEHYDRATED HEREDITARY STOMATOCYTOSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000077485.4
First in ClinVar: Jul 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In affected members from a large Canadian family with dehydrated hereditary stomatocytosis (DHS; 194380), originally reported by Houston et al. (2011), Zarychanski et al. (2012) … (more)
In affected members from a large Canadian family with dehydrated hereditary stomatocytosis (DHS; 194380), originally reported by Houston et al. (2011), Zarychanski et al. (2012) identified heterozygosity for a G-to-A transition at position chr16:88,782,212 (GRCh37) in exon 51 of the PIEZO1 gene, resulting in an arg2456-to-his (R2456H) substitution at a highly conserved residue in the C-terminal region. The mutation was not found in unaffected family members, in dbSNP (build 135), or in approximately 3,200 alleles of the NHLBI Exome Sequencing Project. In a 38-year-old female triathlete with dehydrated hereditary stomatocytosis (DHS; 194380), Andolfo et al. (2013) identified heterozygosity for the R2456H mutation in the PIEZO1 gene. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926305.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957644.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Novel mechanisms of PIEZO1 dysfunction in hereditary xerocytosis. | Glogowska E | Blood | 2017 | PMID: 28716860 |
Hereditary xerocytosis and familial haemolysis due to mutation in the PIEZO1 gene: a simple diagnostic approach. | Sandberg MB | International journal of laboratory hematology | 2014 | PMID: 24314002 |
Dehydrated stomatocytic anemia due to the heterozygous mutation R2456H in the mechanosensitive cation channel PIEZO1: a case report. | Shmukler BE | Blood cells, molecules & diseases | 2014 | PMID: 23973043 |
Recurrent mutation in the PIEZO1 gene in two families of hereditary xerocytosis with fetal hydrops. | Beneteau C | Clinical genetics | 2014 | PMID: 23581886 |
Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels. | Albuisson J | Nature communications | 2013 | PMID: 23695678 |
Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1. | Bae C | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23487776 |
Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. | Andolfo I | Blood | 2013 | PMID: 23479567 |
Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. | Zarychanski R | Blood | 2012 | PMID: 22529292 |
Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred. | Houston BL | Blood cells, molecules & diseases | 2011 | PMID: 21944700 |
Text-mined citations for rs587776988 ...
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.