VCV000010428.22 - ClinVar

NM_002049.4(GATA1):c.647G>A (p.Arg216Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002049.4(GATA1):c.647G>A (p.Arg216Gln)

Variation ID: 10428 Accession: VCV000010428.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 48792371 (GRCh38) [ NCBI UCSC ] X: 48650778 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 28, 2024	Sep 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002049.4:c.647G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002040.1:p.Arg216Gln	missense
NC_000023.11:g.48792371G>A
NC_000023.10:g.48650778G>A
NG_008846.2:g.10798G>A
LRG_559:g.10798G>A
LRG_559t1:c.647G>A	LRG_559p1:p.Arg216Gln
	P15976:p.Arg216Gln

... more HGVS ... less HGVS

Protein change

Other names

R216Q

Canonical SPDI

NC_000023.11:48792370:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA340965 UniProtKB: P15976#VAR_033114 OMIM: 305371.0006 dbSNP: rs104894809 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GATA1		No evidence available	No evidence available	GRCh38 GRCh37	321	495

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Beta-thalassemia-X-linked thrombocytopenia syndrome	Pathogenic (1)	no assertion criteria provided	Oct 1, 2007	RCV000011173.16
Thrombocytopenia, X-linked, with or without dyserythropoietic anemia	Pathogenic (3)	criteria provided, single submitter	-	RCV001542263.14
Diamond-Blackfan anemia GATA binding protein 1 related thrombocytopenia with dyserythropoiesis	Pathogenic (1)	criteria provided, single submitter	Sep 29, 2023	RCV001382887.15
not provided	Pathogenic (3)	criteria provided, single submitter	Dec 1, 2021	RCV001701722.14
X-linked dyserythropoetic anemia with abnormal platelets and neutropenia	Pathogenic (1)	criteria provided, single submitter	Mar 15, 2022	RCV003137511.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002068305.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the GATA1 gene demonstrated a sequence change, c.647G>A, in exon 4 that results in an amino acid change, p.Arg216Gln. This sequence … (more) DNA sequence analysis of the GATA1 gene demonstrated a sequence change, c.647G>A, in exon 4 that results in an amino acid change, p.Arg216Gln. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs104894809). The p.Arg216Gln change affects a highly conserved amino acid residue located in a domain of the GATA1 protein that is known to be functional. The p.Arg216Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in several families with X-linked thrombocytopenia with thalassemia (PMID: 25421114, 12200364, 17209061, 11809723). The p.Arg216Gln amino acid change also occurs in a region of the GATA1 gene where other missense sequence changes have been described in individuals with GATA1-related thrombocytopenia (PMID: 25421114). A functional study demonstrated that the p.Arg216Gln change impairs recruitment of the TAL1 complex, impacting transcriptional activation (PMID: 23704091). Collectively, these evidences indicate that this sequence change pathogenic. (less)
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807192.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP1 strong, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Increased red cell sickling tendency (present) , Long philtrum (present) , Thoracolumbar scoliosis (present) , Joint laxity (present) , Maternal hypertension (present) , Arachnodactyly (present) … (more) Increased red cell sickling tendency (present) , Long philtrum (present) , Thoracolumbar scoliosis (present) , Joint laxity (present) , Maternal hypertension (present) , Arachnodactyly (present) , Maternal seizure (present) , Diarrhea (present) , Premature birth (present) , Clinodactyly of the 5th finger (present) , Pectus excavatum (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Sep 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	GATA binding protein 1 related thrombocytopenia with dyserythropoiesis Diamond-Blackfan anemia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001581843.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 12200364‚ 14691578‚ 17209061‚ 19172521‚ 23704091 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the GATA1 protein (p.Arg216Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the GATA1 protein (p.Arg216Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 12200364, 14691578, 17209061, 19172521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10428). 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 expected to disrupt GATA1 protein function. Experimental studies have shown that this missense change affects GATA1 function (PMID: 12200364, 23704091). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002569325.2 First in ClinVar: Sep 10, 2022 Last updated: Jul 22, 2023 Comment: Submitted to the GoldVariant database by Kathleen Freson, Center for Molecular and Vascular Biology	Clinical Features: Thrombocytopenia (present)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927441.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957287.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Oct 01, 2007)	no assertion criteria provided Method: literature only	THROMBOCYTOPENIA WITH BETA-THALASSEMIA, X-LINKED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031400.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 09, 2022	Publications: PubMed (4) PubMed: 12200364‚ 871527‚ 17209061‚ 17881640 Comment on evidence: Yu et al. (2002) identified an arg216-to-gln (R216Q) mutation in the N finger of GATA1 in a family with X-linked thrombocytopenia with beta-thalassemia (XLTT; 314050). … (more) Yu et al. (2002) identified an arg216-to-gln (R216Q) mutation in the N finger of GATA1 in a family with X-linked thrombocytopenia with beta-thalassemia (XLTT; 314050). The family had previously been reported by Thompson et al. (1977). Tubman et al. (2007) identified an R216Q substitution in affected members of a family with a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of the so-called 'gray platelet syndrome' (139090). In a letter, Balduini et al. (2007) stated that the family reported by Tubman et al. (2007) had a phenotype consistent with X-linked thrombocytopenia with beta-thalassemia (XLTT) and that the classification as 'X-linked gray platelet syndrome' is a misnomer risking confusion in the literature. They noted that deficiency of platelet alpha-granules can be a feature of XLTT. In response, the original authors (Neufeld et al., 2007) agreed that the disorder in the family may be classified as an example of a unique disorder, i.e., XLTT, but endorsed its classification as 'a unique kind of GPS, inherited in X-linked fashion, with platelets indistinguishable by experts from autosomal GPS (at the light microscope and ultrastructure level).' (less)
Pathogenic (Nov 24, 2023)	no assertion criteria provided Method: clinical testing	Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004171679.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
not provided (-)	no classification provided Method: literature only	Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000189416.4 First in ClinVar: Oct 01, 2014 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301538 BookShelf: NBK1364 BookShelf: NBK1364 Comment: Also reported in one family with "gray platelet syndrome".

Comment:

DNA sequence analysis of the GATA1 gene demonstrated a sequence change, c.647G>A, in exon 4 that results in an amino acid change, p.Arg216Gln. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs104894809). The p.Arg216Gln change affects a highly conserved amino acid residue located in a domain of the GATA1 protein that is known to be functional. The p.Arg216Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in several families with X-linked thrombocytopenia with thalassemia (PMID: 25421114, 12200364, 17209061, 11809723). The p.Arg216Gln amino acid change also occurs in a region of the GATA1 gene where other missense sequence changes have been described in individuals with GATA1-related thrombocytopenia (PMID: 25421114). A functional study demonstrated that the p.Arg216Gln change impairs recruitment of the TAL1 complex, impacting transcriptional activation (PMID: 23704091). Collectively, these evidences indicate that this sequence change pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the GATA1 protein (p.Arg216Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 12200364, 14691578, 17209061, 19172521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10428). 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 expected to disrupt GATA1 protein function. Experimental studies have shown that this missense change affects GATA1 function (PMID: 12200364, 23704091). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
GATA1-Related Cytopenia.	Adam MP	-	2023	PMID: 20301538
Analysis of disease-causing GATA1 mutations in murine gene complementation systems.	Campbell AE	Blood	2013	PMID: 23704091
Platelet structural pathology in a patient with the X-linked GATA-1, R216Q mutation.	White JG	Platelets	2009	PMID: 19172521
Why the disorder induced by GATA1 Arg216Gln mutation should be called "X-linked thrombocytopenia with thalassemia" rather than "X-linked gray platelet syndrome".	Balduini CL	Blood	2007	PMID: 17881640
X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation.	Tubman VN	Blood	2007	PMID: 17209061
Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis.	Balduini CL	Thrombosis and haemostasis	2004	PMID: 14691578
X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction.	Yu C	Blood	2002	PMID: 12200364
X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis.	Thompson AR	Blood	1977	PMID: 871527

Text-mined citations for rs104894809 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_002049.4(GATA1):c.647G>A (p.Arg216Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894809 ...