Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV004555187 | SCV005044122 | likely pathogenic | Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema | 2021-08-20 | criteria provided, single submitter | clinical testing | The de novo c.7367G>C (p.Arg2456Pro) missense variant identified in PIEZO1 has not been reported in affected individuals in the literature. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 32, REVEL score = 0.813). A different missense variant (p.Arg2456His) affecting the same Arg2456 residue has been reported in multiple unrelated individuals as well as in large families affected with autosomal dominant dehydrated hereditary stomatocytosis and/or hereditary xerocytosis with fetal hydrops [PMID: 22529292, 23581886, 24314002, 23973043, 29396846, 31624108]. Functional studies have shown that the p.Arg2456His results in gain-of-function of the PIEZO1 channel [23695678, 23479567, 23487776, 28716860]. Another missense variant (p.Arg2456Cys) affecting the same Arg2456 has been reported as homozygous in a patient with autosomal recessive non-immune hydrops fetalis, generalized oedema at birth, and bilateral pleural effusions [PMID: 26333996]. Given the de novo status of c.7367G>C (p.Arg2456Pro), it’s absence from public databases, and published functional importance of the Arg2456 residue, the de novo c.7367G>C (p.Arg2456Pro) missense variant identified in PIEZO1 is reported as Likely Pathogenic. |