Submissions for variant NM_001001548.3(CD36):c.1228_1239del (p.Ile410_Ile413del)

dbSNP: rs550565800

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490260	SCV000267243	likely pathogenic	Platelet-type bleeding disorder 10	2016-03-18	criteria provided, single submitter	reference population
Illumina Laboratory Services, Illumina	RCV000490260	SCV000916211	pathogenic	Platelet-type bleeding disorder 10	2018-01-04	criteria provided, single submitter	clinical testing	The CD36 c.1228_1239delATTGTGCCTATT (p. Ile410_Ile413del) variant, also referred to as c. 1438_1449del, has been reported in five studies in a total of 13 individuals with platelet glycoprotein IV deficiency, including three in a homozygous state, four in a compound heterozygous state, and six in a heterozygous state (Kashiwagi et al. 2001; Tanaka et al. 2001; Li et al. 2014; Masuda et al. 2015; Lo et al. 2016). Typically, individuals homozygous or compound heterozygous for the p.Ile410_Ile413del variant show a type I phenotype with CD36 deficiency on the surface of both platelets and monocytes, while some individuals heterozygous for the variant show a type II phenotype with CD36 deficiency only on the surface of platelets. The p.Ile410_Ile413del variant was found in two unaffected parents of an affected individual and 15/192 control individuals (Kashiwagi et al. 2001; Tanaka et al. 2001; Masuda et al. 2015) in a heterozygous state and is reported at a frequency of 0.01119 in the East Asian population of the Genome Aggregation Database. The 15 control individuals who were heterozygous for the variant had low CD36 expression, but not low enough to be classified as type II. Absence of CD36 surface expression on platelets and monocytes of patient samples was shown by flow cytometry (Kashiwagi et al. 2001; Tanaka et al. 2001; Li et al. 2014; Masuda et al. 2015; Lo et al. 2016). In addition, immunofluorescence experiments with c.1228_1239del expression in HEK293T cells revealed the CD36 protein was retained in the cytoplasm (Kashiwagi et al. 2001). Based on the collective evidence, the p.Ile410_Ile413del variant is classified as pathogenic for platelet glycoprotein IV deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000490260	SCV001499935	likely pathogenic	Platelet-type bleeding disorder 10	2020-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330584	SCV004038410	pathogenic	CD36-related disorder	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: CD36 c.1228_1239del12 (p.Ile410_Ile413del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.00078 in 250154 control chromosomes, predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database. This frequency might reflect a high carrier frequency but does not allow conclusions about variant significance. c.1228_1239del12 has been reported in the literature as a homozygous or a compound heterozygous genotype in multiple individuals affected with features of features of type 1 CD36 deficiency (example, Kashiwagi_2001, Lo_2016, Hao_2021). Some of these studies also reported the variant as a heterozygous genotype in individuals with type II CD36 deficiency. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33942430, 11499670, 25798958, 26528880). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Reproductive Health Research and Development, BGI Genomics	RCV000490260	SCV001142373	likely pathogenic	Platelet-type bleeding disorder 10	2020-01-06	no assertion criteria provided	curation	NM_001001547.2:c.1228_1239delATTGTGCCTATT in the CD36 gene has an allele frequency of 0.011 in East Asian subpopulation in the gnomAD database. The CD36 c.1228_1239delATTGTGCCTATT (p. Ile410_Ile413del) variant, also referred to as c. 1438_1449del, has been reported in multiple individuals with platelet glycoprotein IV deficiency, including in homozygous state (PMID: 26528880) and compound heterozygous state with 329-330del (PMID: 25330908). Immunofluorescence experiments with c.1228_1239del expression in HEK293T cells revealed the CD36 protein was retained in the cytoplasm (PMID: 11499670). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3; PM4; PS3; PP4.