ClinVar Genomic variation as it relates to human health

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.

PP1, PM2, PM4, PS3

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.

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.

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)