rs121908064

Positions:

• chr17-4933367-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000173.7(GP1BA):​c.763A>G​(p.Met255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.50

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain LRRCT (size 61) in uniprot entity GP1BA_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000173.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 17-4933367-A-G is Pathogenic according to our data. Variant chr17-4933367-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4933367-A-G is described in Lovd as [Pathogenic]. Variant chr17-4933367-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.763A>G	p.Met255Val	missense_variant	2/2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.763A>G	p.Met255Val	missense_variant	2/2	1	NM_000173.7	ENSP00000329380	P1
CHRNE	ENST00000649830.1	c.-888+975T>C		intron_variant				ENSP00000496907

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudo von Willebrand disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Impaired ristocetin-induced platelet aggregation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 16, 2021

The GP1BA c.763A>G; p.Met255Val variant (rs121908064), also known as Met239Val in alternate nomenclature, is reported in the literature in multiple individuals affected with pseudo-von Willebrand disease, also called platelet-type von Willebrand disease (Desai 2015, Giannini 2010, Kunishima 1997, Russell 1993, Takahashi 1995). This variant was observed to co-segregate with disease in several small kindreds (Russell 1993, Takahashi 1995) and was confirmed to have arisen de novo in another family (Kunishima 1997). The p.Met255Val variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 255 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.308). However, functional analyses of patient megakaryocytes with this variant exhibit increased binding to von Willebrand factor (Bury 2019). Based on available information, this variant is considered to be pathogenic. References: Bury L et al. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica. 2019 Jul;104(7):1473-1481. PMID: 30655369. Desai DS et al. Elderly female with a personal and family history of a bleeding disorder. Clin Chem. 2015 Jul;61(7):909-12. PMID: 26116638. Giannini S et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica. 2010 Jun;95(6):1021-4. PMID: 19951970. Kunishima S et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease. Blood Coagul Fibrinolysis. 1997 Jul;8(5):311-5. PMID: 9282797. Russell SD and Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID: 8384898. Takahashi H et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. Blood. 1995 Feb 1;85(3):727-33. PMID: 7833477. -

Thrombocytopenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.00095	A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.11	T;.
Sift4G	Uncertain	0.054	T;T
Vest4		0.30
MutPred		0.77		Loss of ubiquitination at K253 (P = 0.0821);Loss of ubiquitination at K253 (P = 0.0821);
MVP		0.65
MPC		0.11
ClinPred		0.14	T
GERP RS		3.6
Varity_R		0.57
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908064; hg19: chr17-4836662;