Submissions for variant NM_000505.4(F12):c.1681-1G>A

gnomAD frequency: 0.00036  dbSNP: rs199988476

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000382012	SCV000456696	likely pathogenic	F12-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.1681-1G>A variant has been reported in at least three studies and is found in a total of one patient in a homozygous state, four patients in a compound heterozygous state and four patients in a heterozygous state (Schloesser et al. 1995; Schloesser et al. 1997; Xu-Cai et al. 2011). The c.1681-1G>A variant was also observed in a heterozygous state in four offspring of one of the compound heterozygote patients. These individuals also exhibited reduced factor XII activity and antigen levels. Gelincik et al. (2015) identified the c.1681-1G>A variant in a heterozygous state in one patient with HAE with normal C1-INH (type 3 HAE). Factor XII levels were within normal limits in this patient. The c.1681-1G>A variant was absent from 74 control individuals and is reported at a frequency of 0.00077 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transcript analysis in two compound heterozygous patients and one homozygous patient with factor XII deficiency demonstrated aberrant splicing, suggesting that the c.1681-1G>A splice acceptor variant results in detectable transcript but unstable protein (Schloesser et al. 1995). Based on the collective evidence, the c.1681-1G>A variant is classified as likely pathogenic for F12-related disorders.
GeneDx	RCV001578121	SCV001805656	pathogenic	not provided	2024-03-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate the variant causes removal of the last exon, resulting in a truncated transcript and unstable protein (PMID: 8528215); Observed in the heterozygous state in an individual with recurrent angioedema and in the compound heterozygous state in individuals with Factor XII deficiency (PMID: 25524745, 9354665); This variant is associated with the following publications: (PMID: 33727708, 21920016, 24029428, 9354665, 23348723, 34426522, 25524745, 31980526, 35866546, 36685169, 8528215)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001578121	SCV002309396	uncertain significance	not provided	2024-06-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the F12 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199988476, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with F12-related conditions (PMID: 8528215, 9354665, 25524745, 33727708). ClinVar contains an entry for this variant (Variation ID: 1166). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000001225	SCV003836435	pathogenic	Factor XII deficiency disease	2022-03-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001578121	SCV004158109	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	F12: PVS1
OMIM	RCV000001225	SCV000021375	pathogenic	Factor XII deficiency disease	1995-07-01	no assertion criteria provided	literature only