Submissions for variant NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)

dbSNP: rs587777450

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623552	SCV000741075	pathogenic	Inborn genetic diseases	2015-09-22	criteria provided, single submitter	clinical testing
Cirak Lab, University Hospital Cologne	RCV000855472	SCV000996602	pathogenic	Fetal akinesia deformation sequence 1; Arthrogryposis multiplex congenita	2019-06-28	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001091982	SCV001248304	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	PIEZO2: PS2, PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP3, PP4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001091982	SCV001447674	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001091982	SCV001874882	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8423615, 24726473, 11152147, 27714920, 31680123, 34038001, 30988732, 32901917, 33610426)
3billion	RCV000125478	SCV002012269	pathogenic	Gordon syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals ((ClinVar ID: VCV000137629.13, PMID:, 24726473 and 27714920, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg2686Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000137630.1, PMID: 24726473, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967, 3Cnet: 0.865, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003147342	SCV003835430	pathogenic	Arthrogryposis, distal, with impaired proprioception and touch	2022-11-07	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV003224865	SCV003920962	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome; Gordon syndrome	2022-10-26	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000224805	SCV004800989	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	2024-03-12	criteria provided, single submitter	curation	The heterozygous p.Arg2799His variant in PIEZO2 was identified by our study in one individual with features including Duane retraction syndrome, congenital ptosis, and vertical gaze abnormalities, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg2799His variant in PIEZO2 has been previously reported in 16 unrelated individuals with PIEZO2-related disorders (PMID: 3658875, PMID: 31680123, PMID: 24726473, PMID: 32901917, PMID: 27714920, PMID: 34958143, PMID: 33060286) and segregated with disease in 13 affected relatives from 5 families (PMID: 36588752, PMID: 24726473, PMID: 27714920). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 24726473, PMID: 32901917, PMID: 34958143). This variant has also been reported in ClinVar (Variation ID: 137629) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. The number of missense variants reported in PIEZO2 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Multiple variants in the same region as the p.Arg2799His variant have been reported in association with disease in ClinVar and in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 24726473; ClinVar Variation ID: 631524, 137631, 137632, 137634). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2686Cys, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 24726473, Variation ID: 137630). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PIEZO2-related disorders. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP1, PP2, PP3 (Richards 2015).
OMIM	RCV000125478	SCV000168930	pathogenic	Gordon syndrome	2014-05-01	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000125478	SCV000281716	pathogenic	Gordon syndrome	2014-06-04	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000224805	SCV000281717	pathogenic	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome	2014-06-04	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091982	SCV001958331	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091982	SCV001974800	pathogenic	not provided		no assertion criteria provided	clinical testing