3-129061809-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_SupportingPP3PP1PP4PM3
This summary comes from the ClinGen Evidence Repository: The c.70T>C (p.Cys24Arg) variant in GP9 is a missense variant predicted to cause substitution of cystine by arginine at amino acid 24. This variant has been detected in at least 14 probands with Bernard-Soulier syndrome. All 14 of these individuals were homozygous for this variant at least 2 of those were confirmed in trans by parental testing (PMIDs:23402648, 21699652, 21173099, 11167791, 29119711; PM3). At least one patient (Patient BSS2.01 in PMID:23402648) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had macrothrombocytopenia which is consistent with Bernard-Soulier syndrome. The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus one affected family member, both with the homozygous genotype with the p.Cys24Arg variant. (PP1; PMID:21173099). The computational predictor REVEL gives a score of 0.732, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). The human copy of this variant failed to rescue thrombocytopenia when expressed in mutant thrombocytopenic zebrafish embryos.In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP1, PP3, PP4, PS3_supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123181/MONDO:0009276/083
Frequency
Consequence
NM_000174.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000780 AC: 19AN: 243690Hom.: 0 AF XY: 0.000106 AC XY: 14AN XY: 132590
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1460698Hom.: 2 Cov.: 32 AF XY: 0.0000606 AC XY: 44AN XY: 726660
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 24 of the GP9 protein (p.Cys24Arg). This variant is present in population databases (rs28933378, gnomAD 0.06%). This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 11167791, 21173099, 21699652, 23402648). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys8Arg. ClinVar contains an entry for this variant (Variation ID: 13533). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys24 amino acid residue in GP9. Other variant(s) that disrupt this residue have been observed in individuals with GP9-related conditions (PMID: 21173099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
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Bernard Soulier syndrome Pathogenic:3
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Variant summary: GP9 c.70T>C (p.Cys24Arg) results in a non-conservative amino acid change located in the Leucine-rich repeat N-terminal domain (IPR000372) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 243690 control chromosomes. c.70T>C has been reported in the literature in multiple individuals (mostly homozygous) affected with Bernard Soulier Syndrome, and has been reported to be a common founder mutation (Sumitha_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Bernard-Soulier syndrome type C Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at