Submissions for variant NM_000128.4(F11):c.1489C>T (p.Arg497Ter)

gnomAD frequency: 0.00003  dbSNP: rs375422404

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000349831	SCV000330014	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	Identified in the heterozygous state or with a second F11 variant in individuals with features of factor XI deficiency in published literature (PMID: 16835901, 26558335, 32853555); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31064749, 31589614, 16835901, 32853555, 26558335)
Fulgent Genetics, Fulgent Genetics	RCV000763125	SCV000893676	pathogenic	Hereditary factor XI deficiency disease	2018-10-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000763125	SCV000899310	likely pathogenic	Hereditary factor XI deficiency disease	2019-02-01	criteria provided, single submitter	research
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000763125	SCV001251505	likely pathogenic	Hereditary factor XI deficiency disease		criteria provided, single submitter	research	The F11 c.1489C>T (p.R497*) nonsense variant is predicted to result in premature protein termination and/or nonsense-mediated decay. This variant has been reported previously as a single heterozygous variant in an individual with Factor XI deficiency (PMID: 16835901) and in the compound heterozygous state in an individual with Factor XI deficiency (PMID: 26558335).
Revvity Omics, Revvity	RCV000763125	SCV002022261	pathogenic	Hereditary factor XI deficiency disease	2021-06-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000349831	SCV002230649	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg497*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs375422404, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with factor XI deficiency (PMID: 16835901, 26558335). ClinVar contains an entry for this variant (Variation ID: 280137). 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.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000763125	SCV002500853	likely pathogenic	Hereditary factor XI deficiency disease		criteria provided, single submitter	clinical testing
Mendelics	RCV000763125	SCV002519642	pathogenic	Hereditary factor XI deficiency disease	2022-05-04	criteria provided, single submitter	clinical testing
DASA	RCV000763125	SCV002588790	pathogenic	Hereditary factor XI deficiency disease	2022-11-03	criteria provided, single submitter	clinical testing	The c.1489C>T;p.(Arg497*) variant creates a premature translational stop signal in the F11 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 280137; PMID: 31064749, PMID: 16835901) - PS4. The variant is present at low allele frequencies population databases (rs375422404 – gnomAD 0.0001193%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003409399	SCV004114003	pathogenic	F11-related disorder	2022-12-22	criteria provided, single submitter	clinical testing	The F11 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant has been reported in individuals with Factor XI deficiency (Mitchell et al. 2006. PubMed ID: 16835901; Table S3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-187207577-C-T). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/280137/). Nonsense variants in F11 are expected to be pathogenic. This variant is interpreted as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000763125	SCV004805724	pathogenic	Hereditary factor XI deficiency disease	2024-03-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273725	SCV001457107	pathogenic	Plasma factor XI deficiency	2020-09-16	no assertion criteria provided	clinical testing