ClinVar Miner

Submissions for variant NM_000132.4(F8):c.3637dup (p.Ile1213fs)

dbSNP: rs387906450
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003657336 SCV002048223 pathogenic not provided 2022-12-05 criteria provided, single submitter clinical testing The F8 c.3637dupA; p.Ile1213AsnfsTer28 variant (rs387906450), also known as codon 1191-1194 insA, 3629insA or 3809insA, is reported in multiple individuals with severe or moderate hemophilia A (Pieneman 1995, Nakaya 2001, Factor VIII database and references therein). This variant is found in the general population with an overall allele frequency of 0.005% (8/163970 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: https://f8-db.eahad.org/ Nakaya S et al. Some factor VIII exon 14 frameshift mutations cause moderately severe haemophilia A. Br J Haematol. 2001 Dec;115(4):977-82. Pieneman WC et al. Screening for mutations in haemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol. 1995 Jun;90(2):442-9.
Neuberg Centre For Genomic Medicine, NCGM RCV004764803 SCV005374787 pathogenic Hereditary factor VIII deficiency disease criteria provided, single submitter clinical testing The frameshift variant c.3637dup(p.Ile1213AsnfsTer28) in F8 gene has been reported in multiple individuals affected with Hemophilia A (Nakaya et. al., 2001; Pieneman et. al., 1995). The observed variant has allele frequency of 0.005% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Isoleucine 1213, changes this amino acid to Asparagine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Ile1213AsnfsTer28. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. However, additional functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.

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