chr16-88715682-C-CCTCCAG

Position:

• chr16-88715682-C-CCTCCAG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_001142864.4(PIEZO1):​c.7488_7489insCTGGAG​(p.Leu2495_Glu2496dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIEZO1 NM_001142864.4 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.425

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88715682-C-CCTCCAG is Pathogenic according to our data. Variant chr16-88715682-C-CCTCCAG is described in ClinVar as [Pathogenic]. Clinvar id is 418948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001142864.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7488_7489insCTGGAG	p.Leu2495_Glu2496dup	inframe_insertion	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7488_7489insCTGGAG	p.Leu2495_Glu2496dup	inframe_insertion	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2024	Published functional studies demonstrate a damaging effect on channel activity by slowing deactivation after stimulation (PMID: 28716860); In-frame duplication of two amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23695678, 31340627, 18377960, 9827909, 28716860, 36864026, 32112123, 32109669, 31019026, 28367341, 35982159, 31040790, 32036089, 30655378, 33074480) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2023	This variant, c.7483_7488dup, results in the insertion of 2 amino acid(s) of the PIEZO1 protein (p.Leu2495_Glu2496dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dehydrated hereditary stomatocytosis (PMID: 23695678, 30187933). It has also been observed to segregate with disease in related individuals. This variant is also known as c.7473_7478dup p.Glu2492_Leu2493dup and E2496ELE. ClinVar contains an entry for this variant (Variation ID: 418948). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PIEZO1 function (PMID: 23695678). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 29, 2022	PP1, PM2, PM4, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	The PIEZO1 c.7483_7488dup; p.Leu2495_Glu2496dup variant (rs587776992), also known as E2496ELE, is reported in the literature in multiple unrelated individuals affected with hereditary xerocytosis, also known as dehydrated hereditary stomatocytosis (DHS) (Albuisson 2013, Grootenboer 1998, More 2020), and has also been shown to co-segregate in a family diagnosed with hereditary high phosphatidylcholine hemolytic anemia (Imashuku 2016). Functional analyses of this variant show gain of PIEZO1 protein function leading to altered mechanotransduction activity of the membrane pore channel (Glogowska 2017). This variant is also reported in ClinVar (Variation ID: 418948). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant duplicates two amino acid residues while leaving the rest of the protein in-frame. 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. PMID: 23695678. Glogowska E et al. Novel mechanisms of PIEZO1 dysfunction in hereditary xerocytosis. Blood. 2017 Oct 19;130(16):1845-1856. PMID: 28716860. Grootenboer S et al. A genetic syndrome associating dehydrated hereditary stomatocytosis, pseudohyperkalaemia and perinatal oedema. Br J Haematol. 1998 103:383-386. PMID: 9827909. Imashuku S et al. PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus. Int J Hematol. 2016 Jul;104(1):125-9. PMID: 26971963. More TA et al. Mechanosensitive Piezo1 ion channel protein (PIEZO1 gene): update and extended mutation analysis of hereditary xerocytosis in India. Ann Hematol. 2020 99:715-727. PMID: 32112123. -

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 14, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 20, 2017	This inframe duplication has previously been reported in eight individuals with hereditary xerocytosis, also known as dehydrated hereditary stomatocytosis (DHS) (PMID: 23695678). The variant is a heterozygous dominant gain of function mutation, as supported by co-segregation patterns and functional studies characterizing its effect on cell permeability (PMID: 23695678). This variant is not present in ExAC or gnomAD reference databases, thus it is presumed rare. Based on the available evidence, the variant was classified as pathogenic. -

Lymphatic malformation 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776992; hg19: chr16-88782090;