Submissions for variant NM_000212.3(ITGB3):c.1914-7C>T

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV004732496	SCV005367713	benign	Glanzmann thrombasthenia	2024-08-20	reviewed by expert panel	curation	The NM_000212.3(ITGB3):c.1914-7C>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing (delta score 0.00). In addition, it occurs at a nucleotide that is not conserved as shown by phyloP score of 0.35 (BP7). The highest population minor allele frequency in gnomAD v4.1 is 0.003668 (275/74966 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). This variant has been reported in ClinVar (SCV003276340.2; SCV004813504.1) but to our knowledge, no occurrence of c.1914-7C>T in individuals affected with Glanzmann Thrombasthenia and no experimental evidence demonstrating its impact on protein function have been reported. In summary this variant is classified as Benign for autosomal recessive Glanzmann thrombasthenia, with ACMG criteria applied as specified by the PD VCEP: BA1, BP7.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002948648	SCV003276340	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994475	SCV004813504	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: ITGB3 c.1914-7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 251358 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. To our knowledge, no occurrence of c.1914-7C>T in individuals affected with Glanzmann Thrombasthenia 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2063683). Based on the evidence outlined above, the variant was classified as uncertain significance.