Submissions for variant NM_000212.3(ITGB3):c.1913+5G>T

dbSNP: rs764779088

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225277	SCV001397545	likely pathogenic	Glanzmann thrombasthenia	2023-05-16	reviewed by expert panel	curation	The NM_000212.3(ITGB3):c.1913+5G>T splice region variant in the exon11/intron 11 boundary has been seen in at least 9 probands from PMIDs: 22190468, 14629479, 34066320, 32237906, 29675921 and 1 unpublished individual from internal laboratory data. GT 36 (PMID: 29675921) has mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). It is reported in gnomAD at a frequency of 0.00016 in the East Asian subpopulation (PM2_NotMet). SpliceAI predicts (score 0.95; PP3) that the wild-type donor splice site is broken and a new donor site is gained 33bp downstream (score 0.37). Sequence analyses revealed that the addition of 38bp to exon 10 due to the use of a cryptic splice site in the downstream intron and an appearance of a stop codon (TGA) in the inserted region just behind exon 10 (PM4). Experimental evidence in COS7 cells shows lack of surface expression of the GPIIb-IIIa complex (PMID: 14629479; PS3_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP3, PM4, PS3_moderate. (VCEP specifications version 2).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558756	SCV004298267	pathogenic	not provided	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the ITGB3 gene. It does not directly change the encoded amino acid sequence of the ITGB3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs764779088, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 14629479, 32237906, 34066320). It has also been observed to segregate with disease in related individuals. This variant is also known as G>T at position 29107 of intron 10. ClinVar contains an entry for this variant (Variation ID: 953041). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ITGB3 function (PMID: 14629479). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of part of intron 11 and introduces a premature termination codon (PMID: 14629479). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003558756	SCV005376733	pathogenic	not provided	2024-04-19	criteria provided, single submitter	clinical testing	RNA analysis and in-vitro assays of this variant demonstrate the downstream utilization of a cryptic donor site with the addition of 38 base pairs and a premature stop codon at the end of exon 10 (PMID: 14629479); Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 22190468, 29675921, 32237906, 14629479, 34066320)