Submissions for variant NM_001377304.1(GFI1B):c.548G>A (p.Arg183Gln)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003236530	SCV003933742	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: GFI1B c.548G>A (p.Arg183Gln) results in a conservative amino acid change located in the Zinc finger C2H2-type (IPR013087) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251220 control chromosomes. To our knowledge, no occurrence of c.548G>A in individuals affected with Platelet-Type Bleeding Disorder 17 and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34662886). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786909	SCV005400134	uncertain significance	Platelet-type bleeding disorder 17	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with platelet-type bleeding disorder 17 (MIM#187900) with autosomal dominant and autosomal recessive inheritance, respectively. Variants that lead to absence of the two terminal zinc fingers of GFI1B have been associated with dominant-negative (PMID: 28550182). For missense variants, there is currently no clear association between variant location and mode of inheritance (PMIDs: 34355501, 32633597, 28880435). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity of bleeding has been reported among family members (PMIDs: 23927492, 28041820). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 36 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated C2H2 type zinc finger domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in five individuals with increased mean platelet volume however it is unclear whether they have other clinical features (PMID: 31992710). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign