ClinVar Miner

Submissions for variant NM_000128.4(F11):c.1858G>C (p.Glu620Gln)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357306 SCV001552736 uncertain significance not provided no assertion criteria provided clinical testing The F11 p.Glu620Gln variant was identified in 1 of 38 proband chromosomes (frequency: 0.0263) from individuals with Factor XI (FXI) deficiency (Rugeri_2010_PMID: 20398070). The variant was found as a novel mutation in one patient, in the compound heterozygous with another variant c.127G>A. Their clinical phenotype was classified as "mild" bleeder. The F11 p.Glu620Gln variant was not identified in ClinVar, Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs148054334) and was found in control databases in 40 of 251334 chromosomes at a frequency of 0.000159 (Genome Aggregation Database Feb 27, 2017). The variant was also observed in the following populations: Latino in 18 of 34578 chromosomes (freq: 0.000521), Other in 3 of 6136 chromosomes (freq: 0.000489), European (non-Finnish) in 16 of 113668 chromosomes (freq: 0.000141), African in 2 of 16250 chromosomes (freq: 0.000123) and Ashkenazi Jewish in 1 of 10080 chromosomes (freq: 0.000099), while the variant was not observed in the East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder and MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity, i.e. a gain of a 3' splice site at c.1860. The p.Glu620 residue is mostly conserved in mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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