Submissions for variant NM_000505.4(F12):c.1025C>T (p.Pro342Leu)

dbSNP: rs2230939

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000268631	SCV000456714	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.
Illumina Laboratory Services, Illumina	RCV000323673	SCV000456715	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000659040	SCV000780844	likely benign	not provided	2017-11-01	criteria provided, single submitter	clinical testing
CeMIA	RCV000268631	SCV001441473	likely benign	Hereditary angioedema type 3		criteria provided, single submitter	clinical testing	The c.1025C>T (p.Pro342Leu) variant, located in exon 10 of the F12 gene, was detected in one type I C1-INH-HAE Polish patient bearing a pathogenic SERPING1 mutation. Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as tolerated and benign, respectively. It has been detected in 0.07692% alleles worldwide (gnomAD database) and its allele frequency is greater than that expected for FXII-HAE. The variant is reported as benign in ClinVar database in patients with FXII-HAE. Taking all the above into account and according to ACMG Guidelines (Criteria: BS1, BP4, BP5, BP6) the variant is considered likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000659040	SCV003249796	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 342 of the F12 protein (p.Pro342Leu). This variant is present in population databases (rs2230939, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with F12-related conditions. ClinVar contains an entry for this variant (Variation ID: 352993). 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 not expected to disrupt F12 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV004619274	SCV005112994	uncertain significance	Inborn genetic diseases	2024-05-26	criteria provided, single submitter	clinical testing	The c.1025C>T (p.P342L) alteration is located in exon 10 (coding exon 10) of the F12 gene. This alteration results from a C to T substitution at nucleotide position 1025, causing the proline (P) at amino acid position 342 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.