ClinVar Miner

Submissions for variant NM_000132.4(F8):c.1063C>T (p.Arg355Ter)

gnomAD frequency: 0.00001  dbSNP: rs137852368
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen RCV000010852 SCV004363658 pathogenic Hereditary factor VIII deficiency disease 2024-02-02 reviewed by expert panel curation The c.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%), which meets the PP4_Moderate and PS4_Very strong criteria. Inhibitors are reported in a few of these patients. One de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID: 29381227, which meets the PS2_Moderate criteria. Two siblings in one family in PMID: 15996930 are noted to have severe HA and the Arg355Ter variant, which meets PP1 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PS2_Moderate, PP1, PM2_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000010852 SCV002049442 pathogenic Hereditary factor VIII deficiency disease 2021-04-21 criteria provided, single submitter clinical testing The F8 c.1063C>T; p.Arg355Ter variant (rs137852368) is reported in numerous individuals with severe hemophilia A (see Factor VIII Variant Database and references therein), and is also reported in ClinVar (Variation ID: 10139). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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 Variant Database: http://f8-db.eahad.org/advance_search_results.php
3billion RCV000010852 SCV003841398 pathogenic Hereditary factor VIII deficiency disease 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000010139 / PMID: 3137981). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000010852 SCV000031079 pathogenic Hereditary factor VIII deficiency disease 1985-05-30 no assertion criteria provided literature only

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