Variant rs587776988 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001142864.4(PIEZO1):c.7367G>A(p.Arg2456His) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2456C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

PIEZO1 links:

PIEZO1 (HGNC:):

PIEZO1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a mutagenesis_site Does not inactivate the protein. gives rise to mechanically activated currents that inactivate more slowly than wild-type currents, suggesting it could shift the channel kinetics from phasic to tonic. (size 0) in uniprot entity PIEZ1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-88715805-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 16-88715804-C-T is Pathogenic according to our data. Variant chr16-88715804-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 linkuse as main transcript	c.7367G>A	p.Arg2456His	missense_variant	51/51	ENST00000301015.14	NP_001136336.2	Q92508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14 linkuse as main transcript	c.7367G>A	p.Arg2456His	missense_variant	51/51	1	NM_001142864.4	ENSP00000301015.9		Q92508

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2024	- -

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2024	- -

Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema;C5703066:Blood group, ER

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 07, 2024

- -

PIEZO1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

The PIEZO1 c.7367G>A variant is predicted to result in the amino acid substitution p.Arg2456His. This variant has been reported in individual(s) with hereditary xerocytosis and functional studies have shown that this variant results in a gain-of-function affect leading to heightened ion channel activation (Andolfo et al 2013. PubMed ID: 23479567; Albuisson et al 2013. PubMed ID: 23695678). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.74

MutPred

0.69

Loss of MoRF binding (P = 0.0719);

MVP

0.54

ClinPred

1.0

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over