chr17-44372408-G-A

Position:

• chr17-44372408-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID:31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575573/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:13 U:1
• Conservation: PhyloP100: 1.67

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3076C>T	p.Arg1026Trp	missense_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3127C>T	p.Arg1043Trp	missense_variant	29/29
ITGA2B	XM_011524750.2	c.3112C>T	p.Arg1038Trp	missense_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3076C>T	p.Arg1026Trp	missense_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.2392C>T	p.Arg798Trp	missense_variant	25/25
ITGA2B	ENST00000587295.5	c.271C>T	p.Arg91Trp	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:13 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Platelet-type bleeding disorder 16 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	This missense ITGA2B variant at c.3076C>T (p.R1026W) was discovered on exome through the Texome Project (R01HG011795). It is reported in the heterozygous state in individuals with ITGA2B-related disorders including autosomal dominant macrothrombocytopenia and autosomal dominant thrombocytopenia with normal platelet size (PMID: 21454453, 29090484, 31064749, 31119735, 32581362). Functional studies suggest this variant is functionally defective (PMID: 21454453, 31691484) (PS3). This variant has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD:25.200) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 28, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 19, 2011	- -

Glanzmann thrombasthenia Pathogenic:2 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 16, 2020	The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID: 31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1026 of the ITGA2B protein (p.Arg1026Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant thrombocytopenia (PMID: 21454453, 29090484, 31119735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R995W. ClinVar contains an entry for this variant (Variation ID: 50233). 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 ITGA2B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ITGA2B function (PMID: 21454453). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 23, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 21454453, 29090484] -

Thrombocytopenia Pathogenic:2

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Sep 01, 2019	The clinical significance is unchnaged from the previous submission. -

ITGA2B-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 17, 2024	The ITGA2B c.3076C>T variant is predicted to result in the amino acid substitution p.Arg1026Trp. This variant (aka R995W) has been reported in several unrelated families to be a cause of autosomal dominant macrothrombocytopenia (Kunishima et al. 2011. PubMed ID: 21454453; Khoriaty et al. 2019. PubMed ID: 31119735). Functional studies show that the p.Arg1026Trp variant causes defective platelet activation (Kunishima et al. 2011. PubMed ID: 21454453). A similar variant, p.Arg1026Gln, has also reported in an individual with Glanzmann thrombasthenia (French et al. 1997. PubMed ID: 9215749) suggesting that amino acid residue p.Arg1026 is important for proper ITGA2B function. This variant has not been reported in a large population database, indicating this variant is rare. In summary, the c.3076C>T variant is categorized as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2024	Variant summary: ITGA2B c.3076C>T (p.Arg1026Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes. c.3076C>T has been reported in the literature in multiple individuals affected with macrothrombocytopenia (Kunishima_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that the variant leads to constitutive activation, membrane ruffling, abnormal cytoplasmic protrusions, and defective proplatelet formation (Kunishima_2011). In addition, knock-in mice with this variant developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation (Akuta_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31691484, 21454453). In ClinVar contains an entry for this variant (Variation ID: 50233). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 15, 2017

- -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.89		Loss of disorder (P = 0.0082);
MVP		0.89
MPC		1.0
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.86

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: rs766503255; hg19: chr17-42449776; COSMIC: COSV52231603; COSMIC: COSV52231603;