Submissions for variant NM_000212.3(ITGB3):c.1801T>A (p.Cys601Ser)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702727	SCV005202745	pathogenic	Glanzmann thrombasthenia 2	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: ITGB3 c.1801T>A (p.Cys601Ser), also reported as Cys575Ser, results in a non-conservative amino acid change located in the EGF-like domain, extracellular domain (IPR013111) 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 4e-06 in 251464 control chromosomes. To our knowledge, no occurrence of c.1801T>A in individuals affected with Glanzmann Thrombasthenia 2 has been reported. However, a different variant affecting the same codon has been classified as pathogenic by our lab for autosomal recessive Glanzmann Thrombasthenia (c.1801T>C, p.Cys601Arg), supporting the critical relevance of codon 601 to ITGB3 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. In vitro assessment of protein surface expression found that this variant reduced surface expression to 9% of wild type controls in a BHK cell line (example, Mor-Cohen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18458089, 22308022). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.