Submissions for variant NM_000128.4(F11):c.166T>C (p.Cys56Arg)

gnomAD frequency: 0.00001  dbSNP: rs121965069

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000012676	SCV000485380	likely pathogenic	Hereditary factor XI deficiency disease	2015-11-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802420	SCV000942251	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs121965069, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 56 of the F11 protein (p.Cys56Arg). This missense change has been observed in individuals with factor XI deficiency (PMID: 11895778, 16079124, 20398070, 28960694). This variant is also known as Cys38Arg. ClinVar contains an entry for this variant (Variation ID: 11901). 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) performed at Invitae indicates that this missense variant is expected to disrupt F11 protein function. Experimental studies have shown that this missense change affects F11 function (PMID: 11895778). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000012676	SCV003823955	pathogenic	Hereditary factor XI deficiency disease	2022-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000802420	SCV005401397	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that cells transfected with C56R contained neither factor XI antigen nor factor XI activity (PMID: 11895778); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19652879, 31043424, 11895778, 16079124, 22159456, 15140127, 27723456, 29367083, 31589614, 32278893, 38003459, 37334785, 28960694, 37252892, 20398070, 10444286)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV005249987	SCV005900602	likely pathogenic	Factor XI deficiency	2024-08-22	criteria provided, single submitter	clinical testing	This variant is also referred to as p.Cys38Arg by legacy nomenclature. The c.166T>C (p.Cys56Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous, compound heterozygous, and homozygous change in patients with factor XI deficiency (PMID: 11895778, 16079124, 28960694, 29367083). Functional studies indicate this variant may lead to impaired protein function (PMID: 11895778). The c.166T>C (p.Cys56Arg) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.0004% (8/1614192), including 1 homozygous individual. Based on the available evidence, c.166T>C (p.Cys56Arg) is classified as Likely Pathogenic.
OMIM	RCV000012676	SCV000032911	pathogenic	Hereditary factor XI deficiency disease	2002-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001273715	SCV001457097	likely pathogenic	Plasma factor XI deficiency	2020-09-16	no assertion criteria provided	clinical testing