Submissions for variant NM_001001548.3(CD36):c.429+2T>C

gnomAD frequency: 0.00220  dbSNP: rs3211893

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
H3Africa Consortium	RCV001777164	SCV002014666	benign	not specified	2020-10-28	criteria provided, single submitter	research	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.092, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330715	SCV004037806	likely pathogenic	CD36-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: CD36 c.429+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 250962 control chromosomes (no homozygotes), predominantly at a frequency of 0.0071 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.429+2T>C has been reported in the literature in at least one individual affected with a suspected inherited thrombocytopenia or platelet function disorder (e.g., Romasko_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 28960434). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely pathogenic, n = 2; benign, n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000991166	SCV004807091	uncertain significance	Platelet-type bleeding disorder 10	2024-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV004591411	SCV005080760	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31345219, 35639915, 27626068, 28960434)
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477775	SCV000536929	likely pathogenic	Platelet-type bleeding disorder 10; Coronary heart disease, susceptibility to, 7; Malaria, susceptibility to	2016-08-06	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000991166	SCV001142372	likely pathogenic	Platelet-type bleeding disorder 10	2020-01-06	no assertion criteria provided	curation	NG_008192.1(NM_001001547.2):c.429+2T>C in the CD36 gene has an allele frequency of 0.007 in African subpopulation, and in 0.0006977 global alleles in the gnomAD database. The c.429+2T>C variant destroys the canonical splice donor site. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2.