rs587777450
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001378183.1(PIEZO2):c.8396G>A(p.Arg2799His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2799G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001378183.1 missense
Scores
Clinical Significance
Conservation
Publications
- Gordon syndromeInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
- arthrogryposis, distal, with impaired proprioception and touchInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
- arthrogryposis- oculomotor limitation-electroretinal anomalies syndromeInheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
- connective tissue disorderInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- Marden-Walker syndromeInheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PIEZO2 | NM_001378183.1 | c.8396G>A | p.Arg2799His | missense_variant | Exon 56 of 56 | ENST00000674853.1 | NP_001365112.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PIEZO2 | ENST00000674853.1 | c.8396G>A | p.Arg2799His | missense_variant | Exon 56 of 56 | NM_001378183.1 | ENSP00000501957.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Gordon syndrome Pathogenic:5
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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. -
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. 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). (N) 0108 - This gene is known to be associated with both recessive (NMD variants) and dominant disease (missense variants) (PMID: 30988732). The phenotypes have been recently regarded as etiologically related (PMID: 24726473). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 52). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (piezo non-specific cation channel, R-Ras-binding domain; NCBI, Decipher, PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. One alternative change to a cysteine has been reported in one patient with Marden-Walker syndrome (PMID: 24726473). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Multiple patients with distal arthrogryposis type 3, and a few with type 5, have been reported with this variant, mostly de novo. (PMID: 24726473; ClinVar; LOVD). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Thec.8057G>A, p.Arg2686His, variant found is located in exon 57 of the PIEZO2 gene. The variant is reported de novo without confirmed paternity in seven literature reports where patients have a consistent phenotype closely related to the consequences of the disease in the gene (PS2/PM6_Very Strong). The variant is reported in the literature in unrelated families, and affected individuals present a phenotype associated with Gordon syndrome (distal arthrogryposis type 3) and with distal arthrogryposis type 5 in other cases (PS4_Moderate). The variant is in a protein domain called Piezo_RRas_bdg (Pfam accession number: PF12166), which is the extracellular domain at the C-terminus of the PIEZO protein that functions as a cation channel and is responsible for the recruitment of R-Ras proteins. Twenty-two pathogenic missense variants in the gene and 48 benign ones are reported in the GnomAD database. Nine (9) of the 22 pathogenic variants are located within the last 3 exons, and only 1 of the 48 is benign; that is, it is a region where many pathogenic variants (hotspot) occur (PM1). PMID: 24726473 reported an amino acid change from arginine to cysteine (another missense change at the same amino acid position) as pathogenic (PM5). The variant found is not present in population databases such as GnomAD, ExAc, or 1000 Genomes (PM2_Supporting). The gene has little tolerance for missense changes (Z score greater than 3). Most of these missense changes are pathogenic in the GnomAD database (PP2). Bioinformatics predictors (Alphamissense, EVE, SIFT, PolyPhen, REVEL) classify the variant as deleted (PP3). The patient's phenotype is consistent with Gordon syndrome (distal arthrogryposis type 3) and distal arthrogryposis type 5, and the PIEZO2 gene is closely associated with the disease, with the variant reported as a cause of both syndromes in the literature (PP4). -
not provided Pathogenic:5
PIEZO2: PS2, PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP3, PP4 -
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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) -
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Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:2
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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). -
Inborn genetic diseases Pathogenic:1
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Fetal akinesia deformation sequence 1;C5779613:Arthrogryposis multiplex congenita Pathogenic:1
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Arthrogryposis, distal, with impaired proprioception and touch Pathogenic:1
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Gordon syndrome;C1862472:Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at