Submissions for variant NM_001378183.1(PIEZO2):c.2725G>C (p.Glu909Gln)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003738661	SCV004559020	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 884 of the PIEZO2 protein (p.Glu884Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PIEZO2 protein function. This variant has not been reported in the literature in individuals affected with PIEZO2-related conditions. This variant is present in population databases (rs369232281, gnomAD 0.004%).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787006	SCV005400236	uncertain significance	Gordon syndrome	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with arthrogryposis. Loss of function has generally been shown to be caused by NMD variants, whereas gain of function has generally been associated with missense variants clustered in the C-terminal (PMID: 30988732). (I) 0108 - This gene is associated with both recessive and dominant disease. NMD variants are associated with recessive disease, while missense variants are associated with dominant disease (PMID: 30988732). The phenotypes have been recently regarded as etiologically related (PMID: 24726473). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 and 3: 15 heterozygotes, 1 homozygote). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign