Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000493236 | SCV000581896 | uncertain significance | not provided | 2017-05-08 | criteria provided, single submitter | clinical testing | The C548Y variant in the KLKB1 gene has been reported previously in prekallikrein deficiency, in an individual with prolonged activated partial thromboplastin time who was compound heterozygous for the C548Y variant and another variant (Lombardi et al., 2003). The C548Y variant is observed in 19/11574 (0.16%) alleles from individuals of Latino background, and in 68/66574 (0.10%) alleles from individuals of Non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The C548Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C548Y as a variant of uncertain significance. |
Institute for Clinical Chemistry and Laboratory Medicine, |
RCV002467436 | SCV002762672 | pathogenic | Inherited prekallikrein deficiency | 2022-12-09 | criteria provided, single submitter | clinical testing | We have identified the variant NM_000892.4(KLKB1):c.1643G>A p.(Cys548Tyr) in three unrelated families, each with an index case of severe prekallikrein (PK) deficiency (Barco et al. PMID: 32202057). Family 1 comprises an index case homozygous for the above variant (<1% PK activity; 10% PK antigen; prolonged aPTT) and its heterozygous parents. The second family consists of a compound heterozygous index case carrying the above variant and the stop gained variant c.1196G>A p.(Trp399*) (<1% PK activity; 6-10% PK antigen; prolonged aPTT) and its daughter heterozygous for c.1643G>A (family first described in PMID: 8259543 as "PK Zurich"). The third case is a single compound heterozygous individual carrying the above variant and c.689T>A p.(Ile230Asn) (<1% PK activity; 9% PK antigen; prolonged aPTT) (first published in a PhD thesis: urn:nbn:de:hebis:30-67544 (in German)). Eight more cases have been reported in the literature by five authors (summarized in PMID: 32202057); some use the old nomenclature Cys529Tyr: Farac presents in her above mentioned PhD thesis two further compound heterozygous cases of Cys548Tyr (with c.451dupT and c.717_719delCTT, respectively) and one homozygous case. Dasanu et al. (PMID: 19773642) reported one, and Francois et al. (PMID: 17413767) two unrelated homozygous cases. Two other compound heterozygous cases are described by Maak et al (also with c.451dupT)(PMID: 19404525) and Lombardi et al (with c.1205G>A)(PMID: 14652634). All of these cases have in common that they have no PK activity (<1%) but, if measured, a residual antigen of 6-10% (CRM+). In addition, this variant has a global MAF of 0.03-0.08% (dbSNP) but reaches a MAF of 0.1% (GnomAD) among Europeans and Latinos, making it the most common PK deficiency-causing variant in these two collectives (Barco et al. PMID: 32202057). Based on all this, this variant is clearly pathogenic (ACMG criteria). |
OMIM | RCV000012815 | SCV000033055 | pathogenic | Prekallikrein deficiency | 2003-12-01 | no assertion criteria provided | literature only |