Submissions for variant NM_000173.7(GP1BA):c.1845_1849del (p.Asn616fs)

gnomAD frequency: 0.00053  dbSNP: rs772106076

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001822812	SCV002070501	uncertain significance	not specified	2021-02-19	criteria provided, single submitter	clinical testing	This sequence change results in an amino acid frameshift and creates a premature stop codon 28 amino acids downstream of the change, p.Asn616Profs*29. This sequence change is present in the last exon of the gene and is not predicted to trigger nonsense mediated decay and may impact only last few amino acids of the resultant protein. This sequence change does not appear to have been previously described in patients with GP1BA-related disorders; however, the majority of the reported variants have been described upstream to this position. This sequence change has been described in the gnomAD database with a population frequency of 0.045% in (dbSNP rs772106076); it has been observed in 125 individuals in the heterozygous state. The functional significance of this sequence change is not known at present. Due to its presence in the last exon of the gene and this truncating variant occurring further downstream than the other truncating variants described to date, the clinical significance of the p.Asn616Profs*29 change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001822812	SCV002570523	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: GP1BA c.1845_1849delTAATG (p.Asn616ProfsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 0.0004 in 249006 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. This frequency does not allow conclusion about variant significance. c.1845_1849delTAATG has been reported in the literature in individuals affected with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29232918, 28748566). ClinVar contains an entry for this variant (Variation ID: 1338214). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002466701	SCV002761966	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Identified as homozygous in one individual and heterozygous in 723 individuals by exome sequencing of 453,787 participants in a Biobank trait association study in the literature (Backman et al., 2021); Frameshift variant predicted to result in protein truncation as the last 37 amino acids are lost and replaced with 28 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 34662886)
Fulgent Genetics, Fulgent Genetics	RCV002503325	SCV002798298	uncertain significance	Bernard Soulier syndrome; Bernard-Soulier syndrome, type A2, autosomal dominant; Nonarteritic anterior ischemic optic neuropathy, susceptibility to; Pseudo von Willebrand disease	2022-01-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407827	SCV004115977	uncertain significance	GP1BA-related disorder	2023-06-12	criteria provided, single submitter	clinical testing	The GP1BA c.1845_1849del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn616Profs*29). To our knowledge, this variant has not been reported in individuals with GP1BA-related disease. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-4837743-CTAATG-C). Loss of function variants in GP1BA have been reported as causative for Bernard-Soulier syndrome, however, to our knowledge, no loss of function variants have been reported downstream of the c.1845_1849del variant (Human Gene Mutation Database, HGMD). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genetics and Molecular Pathology, SA Pathology	RCV002243466	SCV004175235	uncertain significance	Bernard Soulier syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The GP1BA c.1845_1849del variant is classified as VUS (PM2, PM4) This GP1BA c.1845_1849del variant is located in exon 2/2 and is predicted to cause a shift in the reading frame at codon 616. The variant is rare in population databases (gnomAD allele frequency = 0.049%; 76 het and 0 hom in 152270 sequenced alleles; highest frequency = 0.070%, Non-Finnish European population) (PM2). The variant has been reported in dbSNP (rs772106076) and in the HGMD database: CD2127686. It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 1338214).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV002466701	SCV005199785	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002243466	SCV002515583	uncertain significance	Bernard Soulier syndrome	2023-06-01	no assertion criteria provided	research