NM_000173.7(GP1BA):c.206C>T (p.Pro69Leu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 16, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001724415.8

Allele description [Variation Report for NM_000173.7(GP1BA):c.206C>T (p.Pro69Leu)]

NM_000173.7(GP1BA):c.206C>T (p.Pro69Leu)

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.206C>T (p.Pro69Leu)

HGVS:

NC_000017.11:g.4932810C>T
NG_008767.2:g.5516C>T
NM_000173.7:c.206C>TMANE SELECT
NP_000164.5:p.Pro69Leu
LRG_480t1:c.206C>T
LRG_480:g.5516C>T
LRG_480p1:p.Pro69Leu
NC_000017.10:g.4836105C>T
NM_000173.6:c.206C>T

Protein change:

P69L

Links:

dbSNP: rs138825640

NCBI 1000 Genomes Browser:

rs138825640

Molecular consequence:

NM_000173.7:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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glyceraldehyde-3-phosphate dehydrogenase, partial [Hypogymnia tubulosa]
glyceraldehyde-3-phosphate dehydrogenase, partial [Hypogymnia tubulosa]
gi|338173018|gb|AEI83272.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001956253	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002072104	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002765947	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 16, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25370924, 18065693, 32757236, 30349881 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001956253

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Benign

germline

clinical testing

SCV002072104

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 6, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002765947

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 16, 2024)

germline

clinical testing

PubMed (4)
[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	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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome--a case control study.

Bragadottir G, Birgisdottir ER, Gudmundsdottir BR, Hilmarsdottir B, Vidarsson B, Magnusson MK, Larsen OH, Sorensen B, Ingerslev J, Onundarson PT.

Am J Hematol. 2015 Feb;90(2):149-55. doi: 10.1002/ajh.23891. Epub 2014 Nov 24.

PubMed [citation]

PMID:: 25370924

See all PubMed Citations (5)

Details of each submission

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956253.1

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

#	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 Genetic Services Laboratory, University of Chicago, SCV002072104.1

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

Description

DNA sequence analysis of the GP1BA gene demonstrated a sequence change, c.206C>T, in exon 2 that results in an amino acid change, p.Pro69Leu. This sequence change does not appear to have been previously described in individuals with GP1BA-related disorders. This sequence change has been described in the gnomAD database with a low frequency of 0.30% in the non-Finnish European subpopulation (dbSNP rs138825640). The p.Pro69Leu change affects a poorly conserved amino acid residue of the GP1BA protein. The p.Pro69Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of sufficient evidence, the clinical significance of the p.Pro69Leu change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002765947.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GP1BA c.206C>T (p.Pro69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 249278 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GP1BA causing Bernard Soulier Syndrome phenotype (0.00059). c.206C>T has been reported in the literature in a family with macrothrombocytopenia and Bernard-Soulier syndrome. Both of these publications provided evidence supporting benign effect of this variant (example: Ghevaert_2008 and Bragadottir_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25370924, 18065693, 32757236, 30349881). ClinVar contains an entry for this variant (Variation ID: 1285165). Based on the evidence outlined above, the variant was classified as likely benign.

#	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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