Submissions for variant NM_000212.3(ITGB3):c.557C>T (p.Pro186Leu)

gnomAD frequency: 0.00221  dbSNP: rs61736876

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003222153	SCV003915975	likely benign	Glanzmann thrombasthenia	2023-02-08	reviewed by expert panel	curation	The c.557C>T variant in ITGB3 is a missense variant predicted to cause substitution of proline by leucine at amino acid 186. The variant has a high population minor allele frequency in gnomAD v2.1.1 of 0.007131 (178/24960) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024). The computational predictor REVEL gives a score of 0.733, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. It is reported to have an association with lower platelet count in an African American cohorts (PMID: 23103231) but has not been reported in a Glanzmann thrombasthenia patient to our knowledge. In summary, this variant meets the criteria to be classified as a variant of unknown significance - conflicting evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, PP3. (VCEP specifications version 2; date of approval 2/2/2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000862152	SCV001002614	likely benign	not provided	2025-01-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816941	SCV002066536	uncertain significance	not specified	2021-01-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ITGB3 gene demonstrated a sequence change, c.557C>T, in exon 4 that results in an amino acid change, p.Pro186Leu. This sequence change does not appear to have been previously described in individuals with ITGB3-related disorders and has been described in the gnomAD database with a relatively high frequency of 0.71% in the African sub-population (dbSNP rs61736876). The p.Pro186Leu change affects a highly conserved amino acid residue located in a domain of the ITGB3 protein that is known to be functional. The p.Pro186Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro186Leu change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001816941	SCV002555862	uncertain significance	not specified	2022-06-14	criteria provided, single submitter	clinical testing	Variant summary: ITGB3 c.557C>T (p.Pro186Leu) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 150904 control chromosomes in the gnomAD database (v3.1.2), including 3 homozygotes. To our knowledge, no occurrence of c.557C>T in individuals affected with Glanzmann Thrombasthenia 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003965652	SCV004780032	likely benign	ITGB3-related disorder	2019-09-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).