rs1394634674

Variant names:

• chr17-4933277-T-A
• rs1394634674
• NM_000173.7:c.673T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-4933277-T-A
• chr17-4933277-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_Supporting PP4 PP1 PM2_Supporting PM3_Strong PM1

This summary comes from the ClinGen Evidence Repository: NM_000173.7(GP1BA):c.673T>A is a missense variant (p.Cys225Ser), which has been reported in at least three probands with Bernard-Soulier syndrome. Two probands are homozygous for this variant, while another proband is compound heterozygous for this variant and a pathogenic frameshift variant c.1454dup (PM3_Strong). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000005530 (based on 2/60024 alleles) in the Admixed American population, this is below <0.0001114 the threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.599, which is below the ClinGen PD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on GP1BA function. At least one patient (Patient M.L. in PMID:7819107) with this variant had aggregation absent for ristocetin but present for all other agonists and flow cytometry with less than 10% expression of GPIBa (PP4). This variant resides at a disulfide bond residue, Cys225, of GP1BA that is defined as a critical functional domain by the ClinGen PD VCEP (PM1). The variant has been reported to segregate with Bernard-Soulier syndrome in one proband (meeting PP4) plus one affected family member both with the compound heterozygous c.1454dup genotype (PMID:11776304). Finally, surface expression of GP1Ba measured by flow cytometry in CHO cells transiently co-transfected with the c.673T>A variant GP1Ba and wild type GP1Ba showed decreased expression at 0% (<25%) WT levels (PS3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM1, PS3_supporting, PM3_strong, PP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA397318012/MONDO:0009276/079

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 6.25

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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.673T>A	p.Cys225Ser	missense_variant	Exon 2 of 2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.673T>A	p.Cys225Ser	missense_variant	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1065A>T		intron_variant	Intron 1 of 10			ENSP00000496907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461694 Hom.: 0 Cov.: 38 AF XY: 0.00000550 AC XY: 4 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Bernard Soulier syndrome Pathogenic:3

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000173.7(GP1BA):c.673T>A is a missense variant (p.Cys225Ser), which has been reported in at least three probands with Bernard-Soulier syndrome. Two probands are homozygous for this variant, while another proband is compound heterozygous for this variant and a pathogenic frameshift variant c.1454dup (PM3_Strong). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000005530 (based on 2/60024 alleles) in the Admixed American population, this is below <0.0001114 the threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.599, which is below the ClinGen PD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on GP1BA function. At least one patient (Patient M.L. in PMID:7819107) with this variant had aggregation absent for ristocetin but present for all other agonists and flow cytometry with less than 10% expression of GPIBa (PP4). This variant resides at a disulfide bond residue, Cys225, of GP1BA that is defined as a critical functional domain by the ClinGen PD VCEP (PM1). The variant has been reported to segregate with Bernard-Soulier syndrome in one proband (meeting PP4) plus one affected family member both with the compound heterozygous c.1454dup genotype (PMID:11776304). Finally, surface expression of GP1Ba measured by flow cytometry in CHO cells transiently co-transfected with the c.673T>A variant GP1Ba and wild type GP1Ba showed decreased expression at 0% (<25%) WT levels (PS3_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP1, PM1, PS3_supporting, PM3_strong, PP4, PM2_supporting. -

Feb 23, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Feb 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 225 of the GP1BA protein (p.Cys225Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 7819107, 11776304, 21173099). It has also been observed to segregate with disease in related individuals. This variant is also known as T715A (p.Cys209Ser). ClinVar contains an entry for this variant (Variation ID: 435347). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GP1BA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GP1BA function (PMID: 11776304). For these reasons, this variant has been classified as Pathogenic. -

Bernard-Soulier syndrome, type A1 Pathogenic:1

Mar 10, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.84	D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.3	D;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.97
MutPred		0.96		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.93
MPC		0.17
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.89

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: rs1394634674; hg19: chr17-4836572;