NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 7, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001357682.5

Allele description [Variation Report for NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg)]

NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg)

Gene:

PIEZO1:piezo type mechanosensitive ion channel component 1 (Er blood group) [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg)

HGVS:

NC_000016.10:g.88722288C>T
NG_042229.1:g.67933G>A
NM_001142864.4:c.4885G>AMANE SELECT
NP_001136336.2:p.Gly1629Arg
LRG_1137t1:c.4885G>A
LRG_1137:g.67933G>A
LRG_1137p1:p.Gly1629Arg
NC_000016.9:g.88788696C>T
NM_001142864.2:c.4885G>A

Protein change:

G1629R

Links:

dbSNP: rs533910472

NCBI 1000 Genomes Browser:

rs533910472

Molecular consequence:

NM_001142864.4:c.4885G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001553221	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001998177	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 29, 2022)	germline	clinical testing	Citation Link,
SCV004253381	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31680349, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001553221

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV001998177

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Aug 29, 2022)

germline

clinical testing

Citation Link,

SCV004253381

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 7, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations.

Guo W, Lai Y, Yan Z, Wang Y, Nie Y, Guan S, Kuo Y, Zhang W, Zhu X, Peng M, Zhi X, Wei Y, Yan L, Qiao J.

Hum Mutat. 2020 Feb;41(2):432-448. doi: 10.1002/humu.23935. Epub 2019 Nov 11.

PubMed [citation]

PMID:: 31680349

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553221.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PIEZO1 p.Gly1629Arg variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs533910472) and in control databases in 24 of 182774 chromosomes at a frequency of 0.000131 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 22 of 16558 chromosomes (freq: 0.001329) and East Asian in 2 of 12412 chromosomes (freq: 0.000161); it was not observed in the Latino, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Gly1629 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001998177.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31680349)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004253381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant is present in population databases (rs533910472, gnomAD 0.1%). 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 PIEZO1 protein function. ClinVar contains an entry for this variant (Variation ID: 978654). This missense change has been observed in individual(s) with hydrops fetalis (PMID: 31680349). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1629 of the PIEZO1 protein (p.Gly1629Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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