VCV000632008.6 - ClinVar

NM_001001548.3(CD36):c.380C>G (p.Ser127Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001001548.3(CD36):c.380C>G (p.Ser127Ter)

Variation ID: 632008 Accession: VCV000632008.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.11 7: 80661161 (GRCh38) [ NCBI UCSC ] 7: 80290477 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 27, 2019	Apr 20, 2024	Mar 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001001548.3:c.380C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001001548.1:p.Ser127Ter	nonsense
NM_000072.3:c.380C>G	NP_000063.2:p.Ser127Ter	nonsense
NM_001001547.3:c.380C>G	NP_001001547.1:p.Ser127Ter	nonsense
NM_001127443.2:c.380C>G	NP_001120915.1:p.Ser127Ter	nonsense
NM_001127444.2:c.380C>G	NP_001120916.1:p.Ser127Ter	nonsense
NM_001289908.1:c.380C>G	NP_001276837.1:p.Ser127Ter	nonsense
NM_001289909.1:c.380C>G	NP_001276838.1:p.Ser127Ter	nonsense
NM_001289911.2:c.152C>G	NP_001276840.1:p.Ser51Ter	nonsense
NM_001371074.1:c.380C>G	NP_001358003.1:p.Ser127Ter	nonsense
NM_001371075.1:c.380C>G	NP_001358004.1:p.Ser127Ter	nonsense
NM_001371077.1:c.380C>G	NP_001358006.1:p.Ser127Ter	nonsense
NM_001371078.1:c.380C>G	NP_001358007.1:p.Ser127Ter	nonsense
NM_001371079.1:c.278C>G	NP_001358008.1:p.Ser93Ter	nonsense
NM_001371080.1:c.-86C>G		5 prime UTR
NM_001371081.1:c.-103C>G		5 prime UTR
NR_110501.1:n.559C>G		non-coding transcript variant
NC_000007.14:g.80661161C>G
NC_000007.13:g.80290477C>G
NG_008192.1:g.63974C>G

... more HGVS ... less HGVS

Protein change

S127*, S51*, S93*

Other names

Canonical SPDI

NC_000007.14:80661160:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00009

Links

dbSNP: rs201765331 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CD36		-	-	GRCh38 GRCh37	246	269

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Platelet-type bleeding disorder 10	Uncertain significance (1)	criteria provided, single submitter	Nov 21, 2018	RCV000778835.5
Inherited bleeding disorder, platelet-type	Likely pathogenic (1)	criteria provided, single submitter	Mar 24, 2023	RCV004017735.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 21, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Platelet-type bleeding disorder 10 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915228.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Comment: The CD36 c.380C>G (p.Ser127Ter) variant is a stop-gained variant predicted to result in premature termination of the protein, which was observed by ICSL as part … (more) The CD36 c.380C>G (p.Ser127Ter) variant is a stop-gained variant predicted to result in premature termination of the protein, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. (less)
Likely Pathogenic (Mar 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inherited bleeding disorder, platelet-type (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847280.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Ser127X variant in CD36 has not been reported in individuals with CD36-related disorder but it has been reported in ClinVar (Variation ID 632008). It … (more) The p.Ser127X variant in CD36 has not been reported in individuals with CD36-related disorder but it has been reported in ClinVar (Variation ID 632008). It has also been identified in 4/68038 European chromosomes by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 127, which is predicted to lead to a truncated or absent protein. Loss of function of the CD36 gene is an established disease mechanism in autosomal recessive Platelet glycoprotein IV deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive platelet glycoprotein IV deficiency. ACMG/AMP Criteria applied: ACMG: PVS1, PM2_Supporting (less)

Comment:

The CD36 c.380C>G (p.Ser127Ter) variant is a stop-gained variant predicted to result in premature termination of the protein, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.

Comment:

The p.Ser127X variant in CD36 has not been reported in individuals with CD36-related disorder but it has been reported in ClinVar (Variation ID 632008). It has also been identified in 4/68038 European chromosomes by gnomAD v3.1.2 (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 127, which is predicted to lead to a truncated or absent protein. Loss of function of the CD36 gene is an established disease mechanism in autosomal recessive Platelet glycoprotein IV deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive platelet glycoprotein IV deficiency. ACMG/AMP Criteria applied: ACMG: PVS1, PM2_Supporting

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs201765331 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001001548.3(CD36):c.380C>G (p.Ser127Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201765331 ...