VCV000435347.11 - ClinVar

NM_000173.7(GP1BA):c.673T>A (p.Cys225Ser)

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.

(5)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000173.7(GP1BA):c.673T>A (p.Cys225Ser)

Variation ID: 435347 Accession: VCV000435347.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.2 17: 4933277 (GRCh38) [ NCBI UCSC ] 17: 4836572 (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	Aug 28, 2017	Apr 15, 2024	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000173.7:c.673T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000164.5:p.Cys225Ser	missense
NC_000017.11:g.4933277T>A
NC_000017.10:g.4836572T>A
NG_008767.2:g.5983T>A
LRG_480:g.5983T>A
LRG_480t1:c.673T>A	LRG_480p1:p.Cys225Ser

... more HGVS ... less HGVS

Protein change

C225S

Other names

Canonical SPDI

NC_000017.11:4933276:T:A

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA397318012 dbSNP: rs1394634674 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.
GP1BA		-	-	GRCh38 GRCh37	182	240

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.
Bernard-Soulier syndrome, type A1	Pathogenic (1)	criteria provided, single submitter	Mar 10, 2017	RCV000500510.7
Bernard Soulier syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 23, 2024	RCV002222537.6
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 7, 2022	RCV002269281.3
Bernard-Soulier syndrome, type A2, autosomal dominant	Likely pathogenic (1)	criteria provided, single submitter	-	RCV002281099.4

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.
Pathogenic (Mar 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bernard-Soulier syndrome, type A1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595021.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bernard Soulier syndrome Affected status: yes Allele origin: germline, paternal	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002500874.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 Comment: GoldVariant submitter: Jose María Bastida Hospital Universitario Salamanca - IBSAL, Spain	Publications: PubMed (2) PubMed: 34355501‚ 28983057 Observation 1: Clinical Features: Macrothrombocytopenia (present) , severely reduced ristocetin response in aggregation (present) , GPIba expression by flow cytopetry (absent) Family history: no Ethnicity/Population group: Caucasian Observation 2: Clinical Features: Dominant Macrothrombocytopenia (present) , normal aggregation and flow cytometry (present) Family history: yes Ethnicity/Population group: Caucasian
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bernard-Soulier syndrome, type A2, autosomal dominant Affected status: yes Allele origin: germline	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002569927.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 Comment: Submitted to GoldVariant by Jose María Bastida and José Rivera; Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC)	Publications: PubMed (1) PubMed: 7855797 Observation 1: Clinical Features: Macrothrombocytopenia (present) , Presence of grey platelets (present) Family history: yes Sex: female Observation 2: Clinical Features: Macrothrombocytopenia (present) Family history: yes Sex: male Observation 3: Clinical Features: Macrothrombocytopenia (present) Family history: no Sex: male Observation 4: Clinical Features: Macrothrombocytopenia (present) Family history: yes Sex: female Observation 5: Clinical Features: Macrothrombocytopenia (present) Family history: no Sex: male
Pathogenic (Feb 07, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002552657.2 First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect on cell surface and intracellular expression (Gonzlez-Manchn et al., 2001); Not observed at significant frequency in large population … (more) Published functional studies demonstrate a damaging effect on cell surface and intracellular expression (Gonzlez-Manchn et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28983057, 32757236, 11776304, 21173099, 7819107, 24934643, 25539746) (less)
Pathogenic (Feb 23, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bernard Soulier syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004813485.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 21173099‚ 28983057‚ 11776304‚ 7819107 Comment: Variant summary: GP1BA c.673T>A (p.Cys225Ser) results in a non-conservative amino acid change located in the Cysteine-rich flanking region, C-terminal domain (IPR000483) of the encoded protein … (more) Variant summary: GP1BA c.673T>A (p.Cys225Ser) results in a non-conservative amino acid change located in the Cysteine-rich flanking region, C-terminal domain (IPR000483) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249268 control chromosomes (gnomAD). c.673T>A has been reported in the literature in multiple individuals affected with Bernard Soulier Syndrome (e.g. Simsek_1994, Gonzalez-Manchon_2001, Savoia_2011, Bastida_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence finding that the variant results in a loss of protein expression (Gonzalez-Manchon_2001). The following publications have been ascertained in the context of this evaluation (PMID: 7819107, 21173099, 11776304, 28983057). ClinVar contains an entry for this variant (Variation ID: 435347). Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

Published functional studies demonstrate a damaging effect on cell surface and intracellular expression (Gonzlez-Manchn et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 28983057, 32757236, 11776304, 21173099, 7819107, 24934643, 25539746)

Comment:

Variant summary: GP1BA c.673T>A (p.Cys225Ser) results in a non-conservative amino acid change located in the Cysteine-rich flanking region, C-terminal domain (IPR000483) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249268 control chromosomes (gnomAD). c.673T>A has been reported in the literature in multiple individuals affected with Bernard Soulier Syndrome (e.g. Simsek_1994, Gonzalez-Manchon_2001, Savoia_2011, Bastida_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence finding that the variant results in a loss of protein expression (Gonzalez-Manchon_2001). The following publications have been ascertained in the context of this evaluation (PMID: 7819107, 21173099, 11776304, 28983057). ClinVar contains an entry for this variant (Variation ID: 435347). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Title	Author	Journal	Year	Link
GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis.	Megy K	Journal of thrombosis and haemostasis : JTH	2021	PMID: 34355501
Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders.	Bastida JM	Haematologica	2018	PMID: 28983057
Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations.	Savoia A	Haematologica	2011	PMID: 21173099
Compound heterozygosity of the GPIbalpha gene associated with Bernard-Soulier syndrome.	González-Manchón C	Thrombosis and haemostasis	2001	PMID: 11776304
Identification of a homozygous single base pair deletion in the gene coding for the human platelet glycoprotein Ib alpha causing Bernard-Soulier syndrome.	Simsek S	Thrombosis and haemostasis	1994	PMID: 7855797
Cys209 Ser mutation in the platelet membrane glycoprotein Ib alpha gene is associated with Bernard-Soulier syndrome.	Simsek S	British journal of haematology	1994	PMID: 7819107

Text-mined citations for rs1394634674 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000173.7(GP1BA):c.673T>A (p.Cys225Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1394634674 ...