Genetic Variant CD36:p.Ile410_Ile413del (chr7-80673381-ATATTGTGCCTAT-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_001001548.3(CD36):c.1228_1239delATTGTGCCTATT(p.Ile410_Ile413del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,566,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CD36
NM_001001548.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.64

Variant links:

Genes affected

CD36 (HGNC:1663): (CD36 molecule (CD36 blood group)) The protein encoded by this gene is the fourth major glycoprotein of the platelet surface and serves as a receptor for thrombospondin in platelets and various cell lines. Since thrombospondins are widely distributed proteins involved in a variety of adhesive processes, this protein may have important functions as a cell adhesion molecule. It binds to collagen, thrombospondin, anionic phospholipids and oxidized LDL. It directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and it binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport. Mutations in this gene cause platelet glycoprotein deficiency. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2014]

CD36 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001001548.3.

PP5

Variant 7-80673381-ATATTGTGCCTAT-A is Pathogenic according to our data. Variant chr7-80673381-ATATTGTGCCTAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD36	NM_001001548.3 link	c.1228_1239delATTGTGCCTATT	p.Ile410_Ile413del	conservative_inframe_deletion	Exon 13 of 15	ENST00000447544.7	NP_001001548.1	P16671-1A4D1B1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD36	ENST00000447544.7 link	c.1228_1239delATTGTGCCTATT	p.Ile410_Ile413del	conservative_inframe_deletion	Exon 13 of 15	5	NM_001001548.3	ENSP00000415743.2		P16671-1

Frequencies

GnomAD3 genomes

AF:

0.000356

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000784

AC:

196

AN:

250154

Hom.:

AF XY:

0.000688

AC XY:

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0107

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000112

AC:

158

AN:

1414974

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

706964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00393

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.35e-7

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.000355

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0104

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000457

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Platelet-type bleeding disorder 10

Pathogenic:4

Jan 04, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CD36-related disorder

Pathogenic:1

Aug 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over