NM_001142864.4:c.7483_7488dupCTGGAG
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP3
The NM_001142864.4(PIEZO1):c.7483_7488dupCTGGAG(p.Glu2496_Glu2497insLeuGlu) variant causes a conservative 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
Consequence
NM_001142864.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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, 33057194, 36864026, 32112123, 32109669, 31019026, 28367341, 35982159, 31040790, 32036089, 30655378, 33074480) -
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, Nakahara 2023), 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 PMID: 23695678. Glogowska E et al. Novel mechanisms of PIEZO1 dysfunction in hereditary xerocytosis. Blood. 2017 Oct 19. PMID: 28716860. Grootenboer S et al. A genetic syndrome associating dehydrated hereditary stomatocytosis, pseudohyperkalaemia and perinatal oedema. Br J Haematol. 1998 Nov. 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. 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 Apr. PMID: 32112123. Nakahara E et al. Variant spectrum of PIEZO1 and KCNN4 in Japanese patients with dehydrated hereditary stomatocytosis. Hum Genome Var. 2023 Mar 2. PMID: 36864026 -
PP1, PM2_moderate, PM4, PS3 -
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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 autosomal dominant 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 gene product 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. -
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Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Pathogenic:2
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PIEZO1-related disorder Pathogenic:1
This variant is also known as c.7473_7478dup (p.Glu2492_Leu2493dup) and E2496ELE in the literature (PMID: 23695678). This 6-base pair in-frame duplication variant found in exon 51 of 51 leads to the duplication of 2 amino acid residues but preserves the reading frame. This variant has been previously reported as a heterozygous change in multiple unrelated patients with dehydrated hereditary stomatocytosis (PMID: 23695678, 36864026, 32112123, 32036089, 32109669). Functional studies demonstrate that this is a gain-of-function variant, as it leads to increased cell permeability that results in the loss of potassium and subsequent dehydration (PMID: 23695678). The c.7483_7488dup (p.Leu2495_Glu2496dup) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.7483_7488dup (p.Leu2495_Glu2496dup) is classified as Pathogenic. -
Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema;C5703066:Blood group, ER Pathogenic:1
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Lymphatic malformation 6 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at