rs121918452
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePP3PP1PM2_SupportingPS3PM3
This summary comes from the ClinGen Evidence Repository: The ITGB3 missense variant NM_000212.2:c.428T>G replaces the leucine residue with a tryptophan residue (p.Leu143Trp). This variant has been observed in homozygosity in at least 14 individuals reported to have Glanzmann's thrombasthenia (GT) (PMID:9376589, PMID:26096001, PMID:16463284, PMID:36672149; PM3). PMID:16463284 suggests this variant is a founder variant in Indian populations. At least one patient has a phenotype specific for GT (Patient MK, PMID:9376589) with a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3 (PP4_Moderate). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID:26096001; PP1). Additionally, in silico tools predict the variant is damaging to protein function (REVEL score 0.98; PP3) and transient expression of ITGB3 carrying the variant in 293 cells led to a reduced level of αIIbβ3 and αIIb receptor expression on the cell surface (<5% compared to cells expressing wild type ITGB3, PMID:11806996; PS3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3, PM2_supporting, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123252/MONDO:0010119/011
Frequency
Consequence
NM_000212.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGB3 | NM_000212.3 | c.428T>G | p.Leu143Trp | missense_variant | 4/15 | ENST00000559488.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.428T>G | p.Leu143Trp | missense_variant | 4/15 | 1 | NM_000212.3 | P1 | |
ITGB3 | ENST00000571680.1 | c.428T>G | p.Leu143Trp | missense_variant | 4/9 | 1 | |||
ITGB3 | ENST00000696963.1 | c.428T>G | p.Leu143Trp | missense_variant | 4/14 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251478Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2024 | Variant summary: ITGB3 c.428T>G (p.Leu143Trp) 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 allele was found at a frequency of 2e-05 in 251478 control chromosomes (gnomAD). c.428T>G has been reported in the literature in multiple individuals affected with Glanzmann Thrombasthenia 2 (e.g. Basani_1997, Peretz_2006). 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, finding that the variant prevents the export of the protein to the cell surface (Basani_1997). The following publications have been ascertained in the context of this evaluation (PMID: 16463284, 9376589). ClinVar contains an entry for this variant (Variation ID: 13567). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Glanzmann thrombasthenia Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Jun 06, 2024 | The ITGB3 missense variant NM_000212.2:c.428T>G replaces the leucine residue with a tryptophan residue (p.Leu143Trp). This variant has been observed in homozygosity in at least 14 individuals reported to have Glanzmann's thrombasthenia (GT) (PMID: 9376589, PMID: 26096001, PMID: 16463284, PMID: 36672149; PM3). PMID: 16463284 suggests this variant is a founder variant in Indian populations. At least one patient has a phenotype specific for GT (Patient MK, PMID: 9376589) with a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3 (PP4_Moderate). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID: 26096001; PP1). Additionally, in silico tools predict the variant is damaging to protein function (REVEL score 0.98; PP3) and transient expression of ITGB3 carrying the variant in 293 cells led to a reduced level of αIIbβ3 and αIIb receptor expression on the cell surface (<5% compared to cells expressing wild type ITGB3, PMID: 11806996; PS3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3, PM2_supporting, PM3. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 9376589). 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. ClinVar contains an entry for this variant (Variation ID: 13567). This variant is also known as Leu117Trp. This missense change has been observed in individuals with Glanzmann thrombasthenia (PMID: 9376589, 16463284, 26096001). This variant is present in population databases (rs121918452, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the ITGB3 protein (p.Leu143Trp). - |
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | The missense c.428T>G(p.Leu143Trp) variant in ITGB3 gene has been reported in compound heterozygous state in multiple individuals affected with Glanzmann Thrombasthenia (Siddiqi MYJ, et. al., 2023; Peretz H, et. al., 2006). This variant has also been observed to segregate with disease in two affected family members (Haghighi A, et. al., 2016). Evidence of a founder effect was detected in south asian population (Peretz H, et. al., 2006). The variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as pathogenic/Likely pathogenic. The amino acid change p.Leu143Trp in ITGB3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 143 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at