Submissions for variant NM_000505.4(F12):c.418C>G (p.Leu140Val)

gnomAD frequency: 0.00247  dbSNP: rs35515200

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000322122	SCV000456732	likely benign	Factor XII deficiency disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000355853	SCV000456733	benign	Hereditary angioedema type 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000860986	SCV001001178	likely benign	not provided	2025-01-20	criteria provided, single submitter	clinical testing
CeMIA	RCV000355853	SCV001441470	benign	Hereditary angioedema type 3		criteria provided, single submitter	clinical testing	The c.418C>G (p.Leu140Val) variant, located in exon 6 of the F12 gene, was detected in one German patient with type I C1-INH-HAE and two (an Italian and a Polish) U-HAE patients. Family segregation study performed in the two families of U-HAE revealed the mutation in three healthy family members (two males and one female). Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as tolerated and possibly damaging, respectively. It has been detected in 0.2232% alleles worldwide (gnomAD database) and its allele frequency is greater than that expected for FXII-HAE. The mutation is characterized as likely benign in ClinVar database in association to hereditary angioedema. Taking all the above into account and according to ACMG Guidelines (Criteria: BS1, BS2, BP5, BP6) the variant is considered benign.
GeneDx	RCV000860986	SCV003842612	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Identified in one individual from a large cohort with deep vein thrombosis, however no specific clinical or other genetic details were provided for the patient (Lotta et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22353194)
CeGaT Center for Human Genetics Tuebingen	RCV000860986	SCV004158118	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	F12: BP4, BS1
Breakthrough Genomics, Breakthrough Genomics	RCV000860986	SCV005222575	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000860986	SCV001930690	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000860986	SCV001955769	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000860986	SCV001967622	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004555554	SCV004769892	likely benign	F12-related disorder	2022-07-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).