Submissions for variant NM_001378183.1(PIEZO2):c.5227C>T (p.Arg1743Ter)

gnomAD frequency: 0.00001  dbSNP: rs886039821

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760500	SCV000890391	likely pathogenic	not provided	2019-01-22	criteria provided, single submitter	clinical testing	A nonsense variant that is likely pathogenic has been identified in the PIEZO2 gene. The R1685X variant has been previously reported in two unrelated individuals, each harboring a second PIEZO2 variant, with congenital hip dysplasia, finger contractures, foot deformities, severe progressive scoliosis, hypotonia, delayed walking, ataxia, selective loss of discriminative touch perception, and impaired fine motor skills (Chesler et al., 2016). Functional studies showed that R1685X transfected cells had channel currents above baseline noise only, compared to wild type, supporting loss of function (Chesler et al., 2016). The R1685X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Illumina Laboratory Services, Illumina	RCV000256348	SCV001451591	pathogenic	Arthrogryposis, distal, with impaired proprioception and touch	2020-07-28	criteria provided, single submitter	clinical testing	The PIEZO2 c.5053C>T (p.Arg1685Ter) variant is a stop-gained variant that has been reported in one study, in which it is found in a compound heterozygous state in two unrelated individuals with distal arthrogryposis with impaired proprioception and touch (Chesler et al. 2016). The patients presented with congenital hip dysplasia, finger contractures, foot deformities, and progressive scoliosis and had a history of hypotonia, delayed head control, shallow breathing, and delayed walking. Both patients also had selective loss of touch perception and proprioception, leading to ataxia and dysmetria. The p.Arg1685Ter is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. In vitro functional studies showed that p.Arg1685Ter transfected cells had significantly reduced mechanically evoked current, and analysis of PIEZO2 RNA expression in patient cells implied the variant leads to nonsense-mediated decay (Chesler et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Arg1685Ter variant is classified as pathogenic for distal arthrogryposis with impaired proprioception and touch.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760500	SCV001590400	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 265867). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive distal arthrogryposis (PMID: 27653382). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1685*) in the PIEZO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIEZO2 are known to be pathogenic (PMID: 27653382, 27843126).
New York Genome Center	RCV000256348	SCV001761144	likely pathogenic	Arthrogryposis, distal, with impaired proprioception and touch	2020-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987482	SCV004803970	pathogenic	PIEZO2-related disorder	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: PIEZO2 c.5053C>T (p.Arg1685X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.5053C>T has been reported in the literature in two unrelated individuals affected with skeletal malformations, hypotonia, and impaired proprioception who were compound heterozygous with other pathogenic variants (Chesler_2016). This publication reports experimental evidence evaluating an impact on protein function, finding a loss of channel current in cells transfected with the variant protein. The following publication has been ascertained in the context of this evaluation (PMID: 27653382). ClinVar contains an entry for this variant (Variation ID: 265867). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000256348	SCV000322816	pathogenic	Arthrogryposis, distal, with impaired proprioception and touch	2018-09-11	no assertion criteria provided	literature only