rs79208797

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000212.3(ITGB3):c.665T>C(p.Leu222Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ITGB3 links:

ENSG00000259753 (HGNC:):

ENSG00000259753 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain VWFA (size 242) in uniprot entity ITB3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000212.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-47286310-T-C is Pathogenic according to our data. Variant chr17-47286310-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 996163.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB3	NM_000212.3 link	c.665T>C	p.Leu222Pro	missense_variant	Exon 5 of 15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGB3	ENST00000559488.7 link	c.665T>C	p.Leu222Pro	missense_variant	Exon 5 of 15	1	NM_000212.3	ENSP00000452786.2	P05106-1
ITGB3	ENST00000571680.1 link	c.665T>C	p.Leu222Pro	missense_variant	Exon 5 of 9	1		ENSP00000461626.1	I3L4X8
ENSG00000259753	ENST00000560629.1 link	n.629T>C		non_coding_transcript_exon_variant	Exon 5 of 18	2		ENSP00000456711.2	H3BM21
ITGB3	ENST00000696963.1 link	c.665T>C	p.Leu222Pro	missense_variant	Exon 5 of 14			ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 222 of the ITGB3 protein (p.Leu222Pro). This variant is present in population databases (rs79208797, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive Glanzmann thrombasthenia (PMID: 20020534, 20438394, 25539746). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Leu196Pro. ClinVar contains an entry for this variant (Variation ID: 996163). 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 ITGB3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jan 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4_strong, PM2_moderate, PM3_strong, PS3 -

Glanzmann thrombasthenia

Pathogenic:1

Nov 10, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro) is a missense variant which has been previously reported in at least two symptomatic individuals who meet the diagnostic criteria for the GT phenotype (PMIDs:25728920, 11897046). This variant is present at an extremely low MAF of 0.000064 in the Non-Finnish European subpopulation in gnomAD. This variant has been predicted to be deleterious by multiple in silico tools (REVEL score = 0.97). This variant has been reported to occur in the homozygous state in one proband as well as in heterozygous state with another pathogenic variant (p.Cys624Tyr) in a non related proband. Functional studies have demonstrated a deleterious effect on the gene product, preventing the binding of soluble fibrinogen and fibrinogen mimetic antibodies (PMID: 11776310). This variant meets GT specific criteria for PS3, PP4_strong, PM2_supporting, PP3 and PM3_supporting and is therefore classified as Pathogenic. -

Glanzmann thrombasthenia 2

Pathogenic:1

Jan 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ITGB3 c.665T>C (p.Leu222Pro) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of 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 249036 control chromosomes. c.665T>C has been reported in the literature in the homozygous state and compound heterozygous state in individuals affected with Glanzmann Thrombasthenia 2 (e.g. Jallu_2010, Fiore_2012, Sanchez-Guiu_2014). These data indicate that the variant is likely to be associated with disease. At least one publication has reported experimental evidence evaluating an impact on protein function and found that the variant results in the inhibition of alphavbeta3-mediated cell adhesion and clot retraction and demonstrated a reduced surface exposure of the alphaIIbbeta3 receptor, which was inaccordance with the type II thrombasthenic phenotype observed in a homozygous patient (Morel-Kopp_2001). The following publications have been ascertained in the context of this evaluation (PMID: 28983057, 22250950, 20020534, 11776310, 25728920, 25539746). ClinVar contains an entry for this variant (Variation ID: 996163). Based on the evidence outlined above, the variant was classified as pathogenic. -

Glanzmann thrombasthenia 1

Pathogenic:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.8

D;.

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.99

Gain of disorder (P = 0.0455);Gain of disorder (P = 0.0455);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over