NM_000173.7(GP1BA):c.586C>T (p.Gln196Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 8, 2023
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:: RCV000523282.4

Allele description [Variation Report for NM_000173.7(GP1BA):c.586C>T (p.Gln196Ter)]

NM_000173.7(GP1BA):c.586C>T (p.Gln196Ter)

Gene:

GP1BA:glycoprotein Ib platelet subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_000173.7(GP1BA):c.586C>T (p.Gln196Ter)

HGVS:

NC_000017.11:g.4933190C>T
NG_008767.2:g.5896C>T
NM_000173.7:c.586C>TMANE SELECT
NP_000164.5:p.Gln196Ter
LRG_480t1:c.586C>T
LRG_480:g.5896C>T
LRG_480p1:p.Gln196Ter
NC_000017.10:g.4836485C>T
NM_000173.5:c.586C>T

Protein change:

Q196*

Links:

dbSNP: rs371226354

NCBI 1000 Genomes Browser:

rs371226354

Molecular consequence:

NM_000173.7:c.586C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617847	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Aug 31, 2017)	germline	clinical testing	Citation Link,
SCV004343933	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9326229, 9326230, 10089893, 11054083, 24934643, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617847

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Aug 31, 2017)

germline

clinical testing

Citation Link,

SCV004343933

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A dinucleotide deletion results in defective membrane anchoring and circulating soluble glycoprotein Ib alpha in a novel form of Bernard-Soulier syndrome.

Kenny D, Newman PJ, Morateck PA, Montgomery RR.

Blood. 1997 Oct 1;90(7):2626-33.

PubMed [citation]

PMID:: 9326229

Bernard-Soulier syndrome caused by a dinucleotide deletion and reading frameshift in the region encoding the glycoprotein Ib alpha transmembrane domain.

Afshar-Kharghan V, López JA.

Blood. 1997 Oct 1;90(7):2634-43.

PubMed [citation]

PMID:: 9326230

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000617847.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The Q196X variant in the GP1BA gene has been reported previously in association with Bernard-Soulier syndrome, in an affected individual who was compound heterozygous for the Q196X variant and another variant. (Savoia et al., 2014). This variant is predicted to cause loss of normal protein function through protein truncation. The Q196X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret Q196X as a likely pathogenic variant.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004343933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GP1BA protein in which other variant(s) (p.Tyr534Cysfs*82) have been determined to be pathogenic (PMID: 9326229, 9326230, 10089893, 11054083). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 449564). This variant is also known as p.Gln180*. This premature translational stop signal has been observed in individual(s) with Bernard‚ÄìSoulier syndrome (PMID: 24934643). This variant is present in population databases (rs371226354, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln196*) in the GP1BA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 457 amino acid(s) of the GP1BA protein.

#	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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