Variant summary: GP1BA c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249014 control chromosomes (gnomAD). c.515C>T has been reported in the literature in numerous heterozygous individuals affected with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant, and the variant has been shown to segregate with disease in related individuals (e.g., Savoia_2001, Noris_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21933849, 11222377). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000173.7(GP1BA):c.515C>T (p.Ala172Val)
Germline
Classification
Help
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)
Help
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
5
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.515C>T (p.Ala172Val)
Variation ID: 4156 Accession: VCV000004156.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 4933119 (GRCh38) [ NCBI UCSC ] 17: 4836414 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 14, 2024 Jul 25, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000173.7:c.515C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000164.5:p.Ala172Val missense NC_000017.11:g.4933119C>T NC_000017.10:g.4836414C>T NG_008767.2:g.5825C>T LRG_480:g.5825C>T LRG_480t1:c.515C>T LRG_480p1:p.Ala172Val P07359:p.Ala172Val - Protein change
- A172V
- Other names
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A156V
- Canonical SPDI
- NC_000017.11:4933118:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Mar 1, 2001 | RCV000004373.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 19, 2023 | RCV000023565.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2023 | RCV002512752.4 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jun 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Bernard-Soulier syndrome, type A2, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020487.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: GP1BA c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GP1BA c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249014 control chromosomes (gnomAD). c.515C>T has been reported in the literature in numerous heterozygous individuals affected with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant, and the variant has been shown to segregate with disease in related individuals (e.g., Savoia_2001, Noris_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21933849, 11222377). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443701.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this missense change affects GP1BA function (PMID: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as … (more)
Experimental studies have shown that this missense change affects GP1BA function (PMID: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GP1BA protein function. ClinVar contains an entry for this variant (Variation ID: 4156). This variant is also known as Bolzano mutation, Ala156Val. This missense change has been observed in individuals with the classical form of autosomal recessive Bernard-Soulier syndrome. It has also been reported in a heterozygous state with autosomal dominant macrothrombocytopenia in many families and has been considered as the most frequent cause of inherited thrombocytopenia in Italy (PMID: 7690774, 10235425, 11222377, 19067792, 21933849). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 172 of the GP1BA protein (p.Ala172Val). (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Bernard-Soulier syndrome, type A2, autosomal dominant
Affected status: yes
Allele origin:
unknown
|
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500872.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Comment:
GoldVariant submitters: Kathleen Freson, for Molecular and Vascular Biology, Leuven, Belgium and Dr Marie-Christine Morel-Kopp, Northern Blood Research Centre, Sydney, Australia
|
Observation 1:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Observation 2:
Clinical Features:
Macrothrombocytopenia (present)
Observation 3:
Clinical Features:
Macrothrombocytopenia (present) , Bleeding (absent)
Family history: yes
Ethnicity/Population group: Caucasian
Observation 4:
Clinical Features:
Macrothrombocytopenia (present) , Bleeding (absent)
Family history: yes
Ethnicity/Population group: Caucasian
|
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Pathogenic
(Mar 01, 2001)
|
no assertion criteria provided
Method: literature only
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BERNARD-SOULIER SYNDROME, TYPE A1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024544.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with Bernard-Soulier syndrome (231200), Ware et al. (1993) identified a homozygous ala156-to-val substitution (A156V) in the GP Ib alpha protein. This mutation … (more)
In a patient with Bernard-Soulier syndrome (231200), Ware et al. (1993) identified a homozygous ala156-to-val substitution (A156V) in the GP Ib alpha protein. This mutation is situated in a leucine-rich repeat of the protein and is associated with a loss of binding with the von Willebrand factor. In 6 Italian families with autosomal dominant inheritance of mild bleeding symptoms, including petechiae, epistaxis, and mucosal bleeding, Savoia et al. (2001) identified a heterozygous A156V substitution in the GP1BA gene. The findings were consistent with autosomal dominant Bernard-Soulier syndrome (153670). The 6 probands with the A156V mutation and 2 others were found to have a reduction of platelet membrane glycoproteins comparable to that found in a BSS heterozygous condition. (less)
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|
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Pathogenic
(Mar 01, 2001)
|
no assertion criteria provided
Method: literature only
|
BERNARD-SOULIER SYNDROME, TYPE A2, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044856.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with Bernard-Soulier syndrome (231200), Ware et al. (1993) identified a homozygous ala156-to-val substitution (A156V) in the GP Ib alpha protein. This mutation … (more)
In a patient with Bernard-Soulier syndrome (231200), Ware et al. (1993) identified a homozygous ala156-to-val substitution (A156V) in the GP Ib alpha protein. This mutation is situated in a leucine-rich repeat of the protein and is associated with a loss of binding with the von Willebrand factor. In 6 Italian families with autosomal dominant inheritance of mild bleeding symptoms, including petechiae, epistaxis, and mucosal bleeding, Savoia et al. (2001) identified a heterozygous A156V substitution in the GP1BA gene. The findings were consistent with autosomal dominant Bernard-Soulier syndrome (153670). The 6 probands with the A156V mutation and 2 others were found to have a reduction of platelet membrane glycoproteins comparable to that found in a BSS heterozygous condition. (less)
|
Comment:
Comment:
Experimental studies have shown that this missense change affects GP1BA function (PMID: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GP1BA protein function. ClinVar contains an entry for this variant (Variation ID: 4156). This variant is also known as Bolzano mutation, Ala156Val. This missense change has been observed in individuals with the classical form of autosomal recessive Bernard-Soulier syndrome. It has also been reported in a heterozygous state with autosomal dominant macrothrombocytopenia in many families and has been considered as the most frequent cause of inherited thrombocytopenia in Italy (PMID: 7690774, 10235425, 11222377, 19067792, 21933849). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 172 of the GP1BA protein (p.Ala172Val).
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:
Variant summary: GP1BA c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249014 control chromosomes (gnomAD). c.515C>T has been reported in the literature in numerous heterozygous individuals affected with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant, and the variant has been shown to segregate with disease in related individuals (e.g., Savoia_2001, Noris_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21933849, 11222377). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Experimental studies have shown that this missense change affects GP1BA function (PMID: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GP1BA protein function. ClinVar contains an entry for this variant (Variation ID: 4156). This variant is also known as Bolzano mutation, Ala156Val. This missense change has been observed in individuals with the classical form of autosomal recessive Bernard-Soulier syndrome. It has also been reported in a heterozygous state with autosomal dominant macrothrombocytopenia in many families and has been considered as the most frequent cause of inherited thrombocytopenia in Italy (PMID: 7690774, 10235425, 11222377, 19067792, 21933849). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 172 of the GP1BA protein (p.Ala172Val).
Citations for germline classification of this variant
Help| 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 |
| Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). | Noris P | Haematologica | 2012 | PMID: 21933849 |
| Proplatelet formation in heterozygous Bernard-Soulier syndrome type Bolzano. | Balduini A | Journal of thrombosis and haemostasis : JTH | 2009 | PMID: 19067792 |
| Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. | Savoia A | Blood | 2001 | PMID: 11222377 |
| Compound heterozygosity (554-589 del, C515-T transition) in the platelet glycoprotein Ib alpha gene in a patient with a severe bleeding tendency. | Margaglione M | Thrombosis and haemostasis | 1999 | PMID: 10235425 |
| Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome. | Ware J | The Journal of clinical investigation | 1993 | PMID: 7690774 |
| Variant Bernard-Soulier syndrome type bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex. | De Marco L | The Journal of clinical investigation | 1990 | PMID: 1694864 |
Text-mined citations for rs121908065 ...
HelpThese 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 Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.