NM_001142864.4(PIEZO1):c.7180G>A (p.Gly2394Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 14, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001508789.25

Allele description [Variation Report for NM_001142864.4(PIEZO1):c.7180G>A (p.Gly2394Ser)]

NM_001142864.4(PIEZO1):c.7180G>A (p.Gly2394Ser)

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.7180G>A (p.Gly2394Ser)

Other names:

PIEZO1, GLY2394SER (rs201950081)

HGVS:

NC_000016.10:g.88716069C>T
NG_042229.1:g.74152G>A
NM_001142864.4:c.7180G>AMANE SELECT
NP_001136336.2:p.Gly2394Ser
LRG_1137t1:c.7180G>A
LRG_1137:g.74152G>A
LRG_1137p1:p.Gly2394Ser
NC_000016.9:g.88782477C>T
NM_001142864.2:c.7180G>A
NM_001142864.3:c.7180G>A
p.Gly2394Ser

Protein change:

G2394S; GLY2394SER

Links:

OMIM: 611184.0017; dbSNP: rs201950081

NCBI 1000 Genomes Browser:

rs201950081

Molecular consequence:

NM_001142864.4:c.7180G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001715162	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001796639	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	Citation Link,
SCV002047879	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Oct 26, 2023)	germline	clinical testing	Citation Link,
SCV003226329	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Nov 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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 Mayo Clinic Laboratories, Mayo Clinic, SCV001715162.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

#	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		4	not provided	not provided	not provided

From GeneDx, SCV001796639.2

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

Description

Observed in the heterozygous and homozygous states in multiple patients from a serology study, although clinical details were not provided (Karamatic et al. 2023); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 36122374, 32112123, 30187933, 29396846, 34201899)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002047879.2

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

Description

The PIEZO1 c.7180G>A; p.Gly2394Ser variant (rs201950081) is reported in the literature in several individuals affected with dehydrated hereditary stomatocytosis, although its clinical significance was not demonstrated (Andolfo 2021, Russo 2018). This variant is found in the non-Finnish European population with an overall allele frequency of 0.20% (151/74762 alleles, including one homozygote) in the Genome Aggregation Database. The glycine at codon 2394 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.173). Due to limited and conflicting information, the clinical significance of the p.Gly2394Ser variant is uncertain at this time. References: Andolfo I et al. Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients. Genes (Basel). 2021 Jun 23;12(7):958. PMID: 34201899. Russo et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. Am J Hematol. 2018 May;93(5):672-682. PMID: 29396846.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003226329.2

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

#	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: Oct 26, 2024

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