Submissions for variant NM_001102416.3(KNG1):c.1165C>T (p.Arg389Ter)

dbSNP: rs752411996

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz	RCV002467396	SCV002762659	pathogenic	High molecular weight kininogen deficiency	2022-12-06	criteria provided, single submitter	clinical testing	Using medical exome sequencing (confirmation via Sanger sequencing), we identified this variant (NM_001102416.3(KNG1):c.1165C>T p.(Arg389*)) and the canonical splice site variant c.1038+1G>A in compound heterozygosity as the cause of high-molecular-weight kininogen (HK) deficiency in one individual (PMID: 32202057). This case was originally described as being prekallikrein (PK) deficient due to low PK activity (7%) (Tomao et al.; Biochim Clin.; 2015; 39:e7-e9). The HK deficiency could not be investigated on protein level because no patient plasma was available, but the patient was described as having a massively prolonged aPTT, and exome sequencing did not reveal any relevant variants in/around KLKB1. Therefore, the previously observed low PK level is most likely secondary to HK deficiency, as seen elsewere (Adenaeuer et al. PMID: ). The c.1165C>T variant results in a frameshift and, due to its position in exon 10a, in both HK and likely low-molecular-weight kininogen deficiency. In addition, the variant was also found to cause HK deficiency in another family unrelated to our case, also in compound heterozygosity (PMID: 31858768). We classified the variant as pathogenic (ACMG guideline).