rs121908065

Variant names:

• chr17-4933119-C-T
• rs121908065
• NM_000173.7:c.515C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000173.7(GP1BA):​c.515C>T​(p.Ala172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.982
• Publications: 12 publications found

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]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-4933119-C-T is Pathogenic according to our data. Variant chr17-4933119-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.515C>T	p.Ala172Val	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.515C>T	p.Ala172Val	missense_variant	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1223G>A		intron_variant	Intron 1 of 10			ENSP00000496907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461550 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 727064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:3

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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

- -

Jun 19, 2023

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.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. -

Bernard-Soulier syndrome, type A1 Pathogenic:1

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as Bolzano mutation, Ala156Val. ClinVar contains an entry for this variant (Variation ID: 4156). 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: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as Pathogenic. -

Bernard Soulier syndrome;C1280798:Pseudo von Willebrand disease;C1847711:Nonarteritic anterior ischemic optic neuropathy, susceptibility to;C3277076:Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:1

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		0.98
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.0090	D;D
Vest4		0.33
MutPred		0.70		Loss of disorder (P = 0.1431);Loss of disorder (P = 0.1431);
MVP		0.88
MPC		0.52
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.79
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908065; hg19: chr17-4836414;