NM_000174.5(GP9):c.212T>C (p.Phe71Ser) AND Bernard Soulier syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 25, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002222350.4

Allele description [Variation Report for NM_000174.5(GP9):c.212T>C (p.Phe71Ser)]

NM_000174.5(GP9):c.212T>C (p.Phe71Ser)

Gene:

GP9:glycoprotein IX platelet [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.3

Genomic location:

Preferred name:

NM_000174.5(GP9):c.212T>C (p.Phe71Ser)

Other names:

F55S

HGVS:

NC_000003.12:g.129061951T>C
NG_008715.1:g.6150T>C
NM_000174.5:c.212T>CMANE SELECT
NP_000165.1:p.Phe71Ser
NP_000165.1:p.Phe71Ser
LRG_477t1:c.212T>C
LRG_477:g.6150T>C
LRG_477p1:p.Phe71Ser
NC_000003.11:g.128780794T>C
NM_000174.3:c.212T>C
NM_000174.4:c.212T>C
P14770:p.Phe71Ser

Protein change:

F71S; PHE55SER

Links:

UniProtKB: P14770#VAR_024999; OMIM: 173515.0003; dbSNP: rs121918037

NCBI 1000 Genomes Browser:

rs121918037

Molecular consequence:

NM_000174.5:c.212T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Bernard Soulier syndrome (BSS)
Synonyms:: GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF; PLATELET GLYCOPROTEIN Ib DEFICIENCY; Giant platelet syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009276; MeSH: D001606; MedGen: C0005129; Orphanet: 274; OMIM: 231200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002500885	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34355501, 25539746, 25741868
SCV002547882	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 25, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21173099, 21699652, 9163595, 25539746, 9432024 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002500885

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002547882

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 25, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	3	not provided	not provided	3	no	clinical testing

Citations

PubMed

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, Downes K, Morel-Kopp MC, Bastida JM, Brooks S, Bury L, Leinoe E, Gomez K, Morgan NV, Othman M, Ouwehand WH, Perez Botero J, Rivera J, Schulze H, Trégouët DA, Freson K.

J Thromb Haemost. 2021 Oct;19(10):2612-2617. doi: 10.1111/jth.15459. Epub 2021 Aug 5. Erratum in: J Thromb Haemost. 2023 Apr;21(4):1067. doi: 10.1016/j.jtha.2023.01.021.

PubMed [citation]

PMID:: 34355501
PMCID:: PMC9291976

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (7)

Details of each submission

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002500885.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (3)
2	Caucasian	1	not provided	no	clinical testing	PubMed (3)
3	Caucasian	1	not provided	no	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547882.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GP9 c.212T>C (p.Phe71Ser) results in a non-conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248306 control chromosomes (gnomAD). c.212T>C has been reported in the literature in multiple homozygous individuals affected with Bernard Soulier Syndrome (Noris_1997, Suzuki_1997, Sumitha_2011, Sanchez-Guiu_2014, Savoia_2011). 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, however it is suggested that disruption of the the leucine-rich repeat motif impairs surface expression of the GPIb/IX/V complex (Sumitha_2011, Suzuki_1997). Other substitutions at this codon (Phe>Cys) have also been found to impact surface GPIb/IX/V expression (Sumitha_2011). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and the other as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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