ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the F11 protein (p.Gly478Arg). This variant is present in population databases (rs542967227, gnomAD 0.07%). This missense change has been observed in individuals with autosomal recessive factor XI (FXI) deficiency and/or factor XI (FXI) deficiency (PMID: 15842381, 16079124, 16835901, 19652879, 26558335). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly460Arg. ClinVar contains an entry for this variant (Variation ID: 285379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F11 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The missense c.1432G>A (p.Gly478Arg) variant in the F11 gene has been observed in individuals with factor XI (FXI) deficiency (Mitchell, Michael et al.,2006). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and novel in 1000. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Glycine at position 478 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly478Arg in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

The p.Gly478Arg ( historically referred to as Gly460Arg) variant in F11 has been reported in at least 5 homozygous, 2 compound heterozygous, and 2 heterozygous individuals with Hereditary factor XI deficiency disease. Majority of these individuals were noted to have reduced FXI:C and/or FXI:Ag levels (Mitchell 2003 PubMed: 12716376; Saunders 2009 PubMed: 19652879; Downes 2019 PubMed: 31064749; Jayandharan 2005 PMID: 15842381; Mitchell 2006 PMID: 16835901; Pike 2016 PMID: 26558335). It was also observed in ClinVar (Variation ID 285379) and in 0.14% (7/4828) of South Asian gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hereditary factor XI deficiency disease; although, some heterozygotes may present with features. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with factor XI deficiency. Dominant negative missense variants tend to have dominant inheritance patterns (PMID:15026311), while loss of function variants are generally recessive, though symptomatic carriers have been reported (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive cases are more severe than cases involving heterozygous carriers, who may be asymptomatic despite having FXI deficiency (PMID:18446632). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a high degree of variable expression. Intrafamilial variation has been reported (PMID: 32118380). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 26 heterozygotes, 0 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Trypsin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as Gly460Arg, this variant has been reported multiple times pathogenic in ClinVar, and in the literature in individuals with Factor XI deficiency including at least one heterozygous individual (PMID: 15842381, 27710856, 16835901, 16079124). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign