ClinVar Miner

Submissions for variant NM_000132.3(F8):c.222G>A (p.Thr74=) (rs1232517683)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756113 SCV000883831 likely pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing The F8 c.222G>A; p.Thr74Thr variant is reported in one patient presenting with mild hemophilia A and low FVIII levels (FVIII:48%) (Martorell 2015). mRNA analysis showed two bands of different sizes (1012bp and 890 bp), with the smaller resulting from exon 2 skipping which causes a frameshift and early termination codon (Martorell 2015).This variant is found in the general population with a low overall allele frequency of 0.001% (2 out of 200420 alleles) in the Genome Aggregation Database. This variant is a synonymous substitution in exon 2, where the codon change (ACG to ACA) does not alter the protein sequence. However, in support of the functional data, computational algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict this variant creates a cryptic splice acceptor site and may impact splicing. Based on the above information, this variant is considered likely pathogenic. References: Martorell L et al. Molecular characterization of ten F8 splicing mutations in RNA isolated from patient's leucocytes: assessment of in silico prediction tools accuracy. Haemophilia. 2015 Mar;21(2):249-57.

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