Submissions for variant NM_000132.4(F8):c.6505C>T (p.Arg2169Cys)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003405132	SCV004121944	pathogenic	Hereditary factor VIII deficiency disease	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: F8 c.6505C>T (p.Arg2169Cys) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183385 control chromosomes (gnomAD). c.6505C>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A), all with a mild phenotype (e.g. Liu_2000, Silva Pinto_2012, Miller_2012, Inaba_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant resulting in a different amino acid change at the same codon (p.Arg2169His) has been classified as pathogenic, suggesting Arg2169 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 34751920, 10910913, 22103590, 21645180). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.