Submissions for variant NM_000174.5(GP9):c.368C>T (p.Pro123Leu)

gnomAD frequency: 0.00089  dbSNP: rs202229101

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000326317	SCV000440791	uncertain significance	Bernard Soulier syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV001821035	SCV002070996	uncertain significance	not specified	2021-06-17	criteria provided, single submitter	clinical testing	This sequence change has been described in the gnomAD database with a relatively high population frequency of 0.16% in non-Finnish European subpopulation (dbSNP rs202229101). This sequence change was identified in the heterozygous state in two neonates with severe thrombocytopenia (PMID: 28561420). In vitro studies showed that maternal serum reacted with the p.Pro123Leu variant expressed in HEK293 cells. The authors suggested that the alloantigen for the variant was responsible for maternofetal alloimmunization and very severe thrombocytopenia in the neonates. The p.Pro123Leu change affects a highly conserved amino acid residue located in a domain of the GP9 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro123Leu substitution. Due to these contrasting evidences, the clinical significance of the p.Pro123Leu change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV000326317	SCV002789621	uncertain significance	Bernard Soulier syndrome	2021-07-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002520079	SCV003264973	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 123 of the GP9 protein (p.Pro123Leu). This variant is present in population databases (rs202229101, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with neonatal thrombocytopenia (PMID: 28561420). ClinVar contains an entry for this variant (Variation ID: 343220). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000326317	SCV003815104	uncertain significance	Bernard Soulier syndrome	2021-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821035	SCV004122721	uncertain significance	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: GP9 c.368C>T (p.Pro123Leu) results in a non-conservative amino acid change located in the cysteine-rich flanking region, C-terminal domain (IPR000483) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 212334 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in GP9 causing Bernard Soulier Syndrome phenotype (0.00074), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.368C>T has been reported in the literature in the homozygous state in an individual affected with an unspecified bleeding and platelet disorder with impaired platelet aggregation (Westbury_2015) and in the heterozygous state in two severely thrombocytopenic neonates, which appeared to be the result of fetal neonatal alloimmune thrombocytopenia (Jallu_2017). In this case, the father of the two neonates was found to be heterozygous for the variant, whereas the mother carried both wild type alleles. Functional experiments found that cells expressing the variant protein reacted positively with maternal serum in both mAb-specific immobilization of platelet antigens and flow cytometry assays, whereas cells expressing the WT protein did not (Jallu_2017). However, as this finding is also related to the maternal serum having a selective immune response, which could be influenced by other factors, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 28399723, 28561420, 25949529). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000326317	SCV004041777	uncertain significance	Bernard Soulier syndrome	2023-10-09	no assertion criteria provided	clinical testing