Submissions for variant NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)

dbSNP: rs1555621138

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415170	SCV000492762	pathogenic	Distal arthrogryposis	2014-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000487334	SCV000567782	pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect on ion channel inactivation, as human cells with the E2727del variant had slower inactivation and faster recovery in response to a mechanical stimulus, suggesting a gain-of-function effect (Coste et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26259784, 24532247, 23487782, 31965297, 30131872, 31230720, 28974772, 30169785, 27743844, 30988732, 28636944, 35906671, 35698866, 34203046, 11146470, 17345626, Ma2022[Preprint], 27535533, 24726473)
CeGaT Center for Human Genetics Tuebingen	RCV000487334	SCV001248303	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000224433	SCV004047494	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome		criteria provided, single submitter	clinical testing	The inframe deletion variant c.8520_8522del (p.Glu2840del) in PIEZO2 gene has been reported previously as a de novo variant in multiple individuals with distal arthrogryposis type 5 (Coste et al., 2013; McMillin et al, 2014). Functional studies demonstrate that the c.8181_8183delAGA variant is associated with increased channel activity in response to repetitive mechanical signals (Coste et al., 2013).This variant has been reported to the ClinVar database as Pathogenic. The p.Glu2840del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Glu2840del causes deletion of amino acid Glutamic Acid at position 2840. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004649103	SCV005149922	pathogenic	Inborn genetic diseases	2024-06-18	criteria provided, single submitter	clinical testing	The c.8181_8183delAGA (p.E2727del) alteration, located in exon coding 52 of the PIEZO2 gene, results from an in-frame deletion at nucleotide positions c.8181 to c.8183. This results in the deletion of a glutamic acid residue at codon p.2727. for autosomal dominant PIEZO2-related distal arthrogryposis; however, its clinical significance for autosomal recessive PIEZO2-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant PIEZO2-related distal arthrogryposis. It has also been shown to segregate with disease in affected families (Coste, 2013; McMillin, 2014). This amino acid position is highly conserved in available vertebrate species. In an electrophysiological study, this variant showed a functionally abnormal result (Coste, 2013). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000487334	SCV005199010	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000224433	SCV000114918	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	2014-05-01	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000224433	SCV000281713	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	2014-06-04	no assertion criteria provided	research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV001007806	SCV001167496	pathogenic	Gordon syndrome		no assertion criteria provided	research