The relationship between GP6 and Platelet-type bleeding disorder 11, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October 9, 2019. GP6 encodes the platelet membrane glycoprotein receptor for collagen. GPVI plays a critical role in collagen-induced platelet aggregation (PMID: 31351674, 31068042). Platelet-type bleeding disorder 11 is characterized by mild bleeding phenotypes and absent platelet aggregation in response to collagen (PMID: 31351674, 31068042). GP6 was first reported in relation to autosomal recessive Platelet-type bleeding disorder 11 in 2009 (Hermans et al, 2009; PMID: 19552682 and Dumont et al, 2009; PMID: 19549989). At least 5 missense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (9.5 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 19552682, 19549989, 23815599). The mechanism for disease is biallelic loss of function.
Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models and expression studies. GP6-knock-out mice show absent platelet aggregation in response to collagen, similar to human patients (PMIDs: 12738669, 16139873) and platelets from GPVI-deficient mice are functionally abnormal (PMID: 12515812). The expression of GP6 is restricted to platelets and megakaryocytes (PMID: 10961879, 11278467).
In summary, the GP6 - Platelet-type Bleeding Disorder 11 gene-disease relationship is definitive. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October 23, 2019 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.