ClinVar Genomic variation as it relates to human health
NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)
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_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)
Variation ID: 137629 Accession: VCV000137629.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18p11.22 18: 10671729 (GRCh38) [ NCBI UCSC ] 18: 10671726 (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 Oct 11, 2015 Aug 4, 2024 Mar 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001378183.1:c.8396G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365112.1:p.Arg2799His missense NM_022068.4:c.8057G>A NP_071351.2:p.Arg2686His missense NC_000018.10:g.10671729C>T NC_000018.9:g.10671726C>T NG_034005.1:g.482034G>A Q9H5I5:p.Arg2686His - Protein change
- R2686H, R2799H
- Other names
- NM_001378183.1(PIEZO2):c.8396G>A
- p.Arg2799His
- Canonical SPDI
- NC_000018.10:10671728: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
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
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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
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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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PIEZO2 | - | - |
GRCh38 GRCh37 |
1000 | 1121 |
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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Pathogenic (3) |
criteria provided, single submitter
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Oct 2, 2021 | RCV000125478.8 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 12, 2024 | RCV000224805.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2015 | RCV000623552.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 28, 2019 | RCV000855472.2 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2022 | RCV001091982.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV003224865.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2022 | RCV003147342.2 |
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
(May 02, 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: SCV001874882.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8423615, 24726473, 11152147, 27714920, 31680123, 34038001, 30988732, 32901917, 33610426) (less)
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Pathogenic
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arthrogryposis, distal, with impaired proprioception and touch
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835430.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jun 28, 2019)
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criteria provided, single submitter
Method: research
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Arthrogryposis multiplex congenita
Fetal akinesia sequence
Affected status: yes
Allele origin:
unknown
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Cirak Lab, University Hospital Cologne
Accession: SCV000996602.1
First in ClinVar: Nov 08, 2019 Last updated: Nov 08, 2019 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Turkish
Geographic origin: Turkey
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447674.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Arthrogryposis multiplex congenita (present) , Short stature (present)
Sex: female
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Gordon syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002012269.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals ((ClinVar ID: VCV000137629.13, PMID:, 24726473 and 27714920, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg2686Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000137630.1, PMID: 24726473, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967, 3Cnet: 0.865, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Macrocephaly (present) , Failure to thrive (present) , Intellectual disability (present) , Delayed fine motor development (present) , Clubfoot (present) , Delayed gross motor development … (more)
Macrocephaly (present) , Failure to thrive (present) , Intellectual disability (present) , Delayed fine motor development (present) , Clubfoot (present) , Delayed gross motor development (present) , Premature birth (present) , Facial palsy (present) , Fetal growth restriction (present) , Abnormality of the outer ear (present) , Flexion contracture (present) , Delayed speech and language development (present) , Micrognathia (present) , Depressed nasal bridge (present) , Epicanthus (present) , Orofacial cleft (present) , Patent ductus arteriosus (present) , Hydrocephalus (present) , Craniosynostosis syndrome (present) , Short stature (present) , Growth delay (present) (less)
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Pathogenic
(Sep 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741075.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Robin sequence (present) , Micrognathia (present) , Retrognathia (present) , Cleft palate (present) , Feeding difficulties (present) , Short stature (present) , Camptodactyly (present) , … (more)
Robin sequence (present) , Micrognathia (present) , Retrognathia (present) , Cleft palate (present) , Feeding difficulties (present) , Short stature (present) , Camptodactyly (present) , Cystic hygroma (present) , Pterygium (present) , Precocious puberty (present) , Scoliosis (present) , Prominent forehead (present) , Prominent supraorbital ridges (present) , Narrow nasal bridge (present) , Malar flattening (present) , Posteriorly rotated ears (present) , Low-set ears (present) , Low posterior hairline (present) , Asymmetry of the thorax (present) , Intrauterine growth retardation (present) , Abnormality of the spinal cord (present) , Short chin (present) , Flexion contracture of finger (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Oct 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gordon syndrome
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV003920962.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Method: Exome sequencing
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248304.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Comment:
PIEZO2: PS2, PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP3, PP4
Number of individuals with the variant: 5
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Pathogenic
(Mar 12, 2024)
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criteria provided, single submitter
Method: curation
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Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV004800989.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The heterozygous p.Arg2799His variant in PIEZO2 was identified by our study in one individual with features including Duane retraction syndrome, congenital ptosis, and vertical gaze … (more)
The heterozygous p.Arg2799His variant in PIEZO2 was identified by our study in one individual with features including Duane retraction syndrome, congenital ptosis, and vertical gaze abnormalities, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg2799His variant in PIEZO2 has been previously reported in 16 unrelated individuals with PIEZO2-related disorders (PMID: 3658875, PMID: 31680123, PMID: 24726473, PMID: 32901917, PMID: 27714920, PMID: 34958143, PMID: 33060286) and segregated with disease in 13 affected relatives from 5 families (PMID: 36588752, PMID: 24726473, PMID: 27714920). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 24726473, PMID: 32901917, PMID: 34958143). This variant has also been reported in ClinVar (Variation ID: 137629) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. The number of missense variants reported in PIEZO2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Multiple variants in the same region as the p.Arg2799His variant have been reported in association with disease in ClinVar and in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 24726473; ClinVar Variation ID: 631524, 137631, 137632, 137634). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2686Cys, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 24726473, Variation ID: 137630). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PIEZO2-related disorders. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP2, PP3 (Richards 2015). (less)
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Pathogenic
(Jun 04, 2014)
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no assertion criteria provided
Method: research
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Gordon syndrome
Affected status: yes
Allele origin:
de novo
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000281716.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Jun 04, 2014)
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no assertion criteria provided
Method: research
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Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
Affected status: yes
Allele origin:
de novo
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000281717.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
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Pathogenic
(May 01, 2014)
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no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS, DISTAL, TYPE 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000168930.4
First in ClinVar: Jun 23, 2014 Last updated: Sep 14, 2018 |
Comment on evidence:
In affected individuals from 9 families with distal arthrogryposis type 3 (DA3; 114300), including the family originally reported by Becker and Splitt (2001), McMillin et … (more)
In affected individuals from 9 families with distal arthrogryposis type 3 (DA3; 114300), including the family originally reported by Becker and Splitt (2001), McMillin et al. (2014) identified heterozygosity for a c.8057G-A transition in exon 52 of the PIEZO2 gene, resulting in an arg2686-to-his (R2686H) substitution. The mutation, which segregated with disease in each family, was not present in the ESP6500 or 1000 Genomes Project databases, or in more than 1,400 chromosomes from internal databases. In addition, 2 probands who had been diagnosed with distal arthrogryposis type 5 (DA5; 108145), 1 of whom was the Dutch patient described by Schrander-Stumpel et al. (1993), were found to be heterozygous for R2686H. Neither proband exhibited the characteristic DA3 feature of cleft palate; however, given the reduced penetrance of cleft palate in DA3, McMillin et al. (2014) suggested that the correct diagnosis in the 2 cases was DA3 rather than DA5. The authors also noted that the presence of cleft palate was significantly associated with R2686H (p less than 0.0001). In a father and 2 sons with DA3, who also exhibited mild intellectual disability and psychomotor delay, Alisch et al. (2017) identified heterozygosity for the recurrent R2686H mutation. (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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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: SCV001958331.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974800.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 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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The genomic and clinical landscape of fetal akinesia. | Pergande M | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31680123 |
Familial Gordon syndrome associated with a PIEZO2 mutation. | Alisch F | American journal of medical genetics. Part A | 2017 | PMID: 27714920 |
Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. | McMillin MJ | American journal of human genetics | 2014 | PMID: 24726473 |
A family with distal arthrogryposis and cleft palate: possible overlap between Gordon syndrome and Aase-Smith syndrome. | Becker K | Clinical dysmorphology | 2001 | PMID: 11152147 |
Arthrogryposis, ophthalmoplegia, and retinopathy: confirmation of a new type of arthrogryposis. | Schrander-Stumpel CT | Journal of medical genetics | 1993 | PMID: 8423615 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7e0fa869-79be-4256-a497-d565d1f18431 | - | - | - | - |
Text-mined citations for rs587777450 ...
HelpRecord last updated Aug 04, 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.