ClinVar Miner

Submissions for variant NM_001142864.4(PIEZO1):c.7367G>A (p.Arg2456His)

dbSNP: rs587776988
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001388579 SCV000885906 pathogenic not provided 2023-04-14 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000049232 SCV001523814 pathogenic Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema 2019-07-20 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001388579 SCV001589630 pathogenic not provided 2023-12-18 criteria provided, single submitter clinical testing 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.
GeneDx RCV001388579 SCV002098177 pathogenic not provided 2022-02-14 criteria provided, single submitter clinical testing 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)
Revvity Omics, Revvity Omics RCV001388579 SCV003822863 pathogenic not provided 2023-02-28 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001388579 SCV004026674 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
OMIM RCV000049232 SCV000077485 pathogenic Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema 2013-05-09 no assertion criteria provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001388579 SCV001926305 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001388579 SCV001957644 pathogenic not provided no assertion criteria provided clinical testing

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