ClinVar Miner

Submissions for variant NM_000505.3(F12):c.983C>A (p.Thr328Lys) (rs118204456)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000222890 SCV000271369 pathogenic Hereditary angioneurotic edema 2015-09-17 criteria provided, single submitter clinical testing The p.Thr328Lys variant in F12 has been reported in at least 18 individuals with hereditary angioedema type 3 (HAE 3), and segregated with disease in >35 affect ed relatives (Dewald 2006, Cichon 2006, Martin 2007, Duan 2009, Picone 2010, Mor eno 2015, Firinu 2015). However, many apparently unaffected family members were also found to carry this variant, which has been partially attributed to both ag e- and sex-dependent penetrance (Dewald 2006, Martin 2007). Of note, the HAE 3 p henotype appears to be estrogen-dependent and males who carry this variant were rarely affected (Dewald 2006, Martin 2007). The p.Thr328Lys variant was also ide ntified in 1/9444 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs118204456). Please note that for disease s with clinical variability or reduced penetrance, pathogenic variants may be pr esent at a low frequency in the general population. In summary, this variant mee ts our criteria to be classified as pathogenic for HAE 3 in an autosomal dominan t manner based upon segregation studies and low frequency in controls.
GeneDx RCV000255869 SCV000321621 pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The T328K variant has been published previously in association with hereditary angioedema (Cichon et al., 2006; Dewald et al., 2006; Bjorkqvist et al., 2015). It was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. T328K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant at the same residue (T328R) has also been reported in the Human Gene Mutation Database in association with hereditary angioedema (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the T328K variant have shown that it leads to loss of glycosylation and increased microvascular leakage upon contact (Bjorkqvist et al., 2015).
Fulgent Genetics,Fulgent Genetics RCV000763138 SCV000893698 pathogenic Factor XII deficiency disease; Hereditary angioneurotic edema with normal C1 esterase inhibitor activity 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000001228 SCV000021378 pathogenic Hereditary angioneurotic edema with normal C1 esterase inhibitor activity 2009-04-01 no assertion criteria provided literature only

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