18-10671729-C-T

Position:

• chr18-10671729-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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. 12/19 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. R2799C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.87

Genes affected

PIEZO2 (HGNC:26270): (piezo type mechanosensitive ion channel component 2) The protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels. These channels serve to connect mechanical forces to biological signals. The encoded protein quickly adapts MA currents in somatosensory neurons. Defects in this gene are a cause of type 5 distal arthrogryposis. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-10671730-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 137630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 18-10671729-C-T is Pathogenic according to our data. Variant chr18-10671729-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 137629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10671729-C-T is described in Lovd as [Pathogenic]. Variant chr18-10671729-C-T is described in Lovd as [Likely_pathogenic]. Variant chr18-10671729-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.8396G>A	p.Arg2799His	missense_variant	56/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.8396G>A	p.Arg2799His	missense_variant	56/56		NM_001378183.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PIEZO2: PS2, PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Gordon syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jun 04, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jun 04, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 12, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2015

- -

Fetal akinesia deformation sequence 1;C5779613:Arthrogryposis multiplex congenita Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Cirak Lab, University Hospital Cologne

Jun 28, 2019

- -

Arthrogryposis, distal, with impaired proprioception and touch Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 07, 2022

- -

Gordon syndrome;C1862472:Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.4	.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
REVEL	Pathogenic	0.97
Sift4G	Pathogenic	0.0010	D;D;D;D
Vest4		0.85
MVP		0.10
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777450; hg19: chr18-10671726;