Submissions for variant NM_000892.5(KLKB1):c.451dup (p.Ser151fs)

dbSNP: rs560588447

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000883758	SCV001027090	benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz	RCV002466263	SCV002761246	pathogenic	Inherited prekallikrein deficiency	2022-12-13	criteria provided, single submitter	clinical testing	We were able to detect this variant, NM_000892.4(KLKB1):c.451dupT p.(Ser151Phefs*34), in homozygosity in three unrelated individuals with severe prekallikrein deficiency and prolonged aPTT (Barco et al. PMID: 32202057; Adenaeuer et al. PMID: 33073460) (<1% PK activity and antigen level). Functional assays of one individual were originally published by Nazir et al. (DOI: 10.15406/htij.2019.07.00197). This is a frameshift variant in exon 5, resulting in a premature stop codon and virtually no detectable prekallikrein activity or antigen (CRM-). Other known cases with KLKB1 c.451dupT in the literature: This variant was first identified in a homozygous case (urn:nbn:de:hebis:30-67544 (German doctoral thesis) and by Maak et al. in a compound heterozygous prekallikrein deficient individual (PMID: 19404525 (paper in German)). Homozygosity for this variant was also detected in an African American case (PMID: 31984307) and an Indian case with PK deficiency (PMID: 34847617)(both did not adhere to HGVS nomenclature, but depicted sequences match). In summary, this variant is to be classified as pathogenic (ACMG criteria) and leads to no detectable PK activity or antigen. It is rare in many ethnicities (0.1-0.6%) but reaches a MAF of 1-2% in several African collectives (dbSNP), making it by far the most frequent PK deficiency causing variant. This variant alone causes one case of PK deficiency in every ~7000 people in native African collectives and collectives of African origin studied (PMID: 33073460).
GeneDx	RCV000883758	SCV003935435	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 19404525, 31984307, 32202057, 34847617, 33073460)
CeGaT Center for Human Genetics Tuebingen	RCV000883758	SCV004151881	benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	KLKB1: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003955868	SCV004775353	pathogenic	KLKB1-related disorder	2023-12-04	criteria provided, single submitter	clinical testing	The KLKB1 c.451dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser151Phefs*34). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with prekallikrein deficiency (Maak et al. 2009. PubMed ID: 19404525; Nazir and Pathare 2019. Hematol Transfus Int J. 2019;7(1):11-15 DOI: 10.15406/htij.2019.07.00197; Dasgupta et al. 2020. PubMed ID: 31984307; Barco et al. 2020. PubMed ID: 322022057; Adenaeuer et al. 2020. PubMed ID: 33073460; Abraham et al. 2021. PubMed ID: 34847617) and has been reported to co-segregate with the disorder in at least one family (Maak et al. 2009. PubMed ID: 19404525). This variant is reported in 1.4% of alleles in individuals of African descent in gnomAD and is the variant primarily responsible for the elevated prevalence of prekallikrein deficiency in this subpopulation (Barco et al. 2020. PubMed ID: 322022057; Adenaeuer et al. 2020. PubMed ID: 33073460). Frameshift variants in KLKB1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV002274107	SCV002559810	pathogenic	Prekallikrein deficiency	2022-08-09	no assertion criteria provided	literature only