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NM_001102416.3(KNG1):c.306+2T>A AND High molecular weight kininogen deficiency

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 4, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003325634.1

Allele description [Variation Report for NM_001102416.3(KNG1):c.306+2T>A]

NM_001102416.3(KNG1):c.306+2T>A

Gene:
KNG1:kininogen 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q27.3
Genomic location:
Preferred name:
NM_001102416.3(KNG1):c.306+2T>A
HGVS:
  • NC_000003.12:g.186720217T>A
  • NG_016009.1:g.7909T>A
  • NM_000893.4:c.306+2T>A
  • NM_001102416.3:c.306+2T>AMANE SELECT
  • NM_001166451.2:c.306+2T>A
  • LRG_598t1:c.306+2T>A
  • LRG_598t2:c.306+2T>A
  • LRG_598:g.7909T>A
  • NC_000003.11:g.186438006T>A
Molecular consequence:
  • NM_000893.4:c.306+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001102416.3:c.306+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001166451.2:c.306+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
High molecular weight kininogen deficiency
Synonyms:
FITZGERALD TRAIT; Flaujeac factor deficiency; Reduced kininogen activity; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009234; MedGen: C0272340; OMIM: 228960; Human Phenotype Ontology: HP:0005527

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004031439Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 4, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes31not providednot providednot providedclinical testing

Citations

PubMed

Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency-causing KNG1 variants, and estimated prevalence.

Adenaeuer A, Barco S, Trinchero A, Krutmann S, Nazir HF, Ambaglio C, Rocco V, Pancione Y, Tomao L, Ruiz-Sáez A, Echenagucia M, Alesci S, Sollfrank S, Ezigbo ED, Häuser F, Lackner KJ, Lämmle B, Rossmann H.

J Thromb Haemost. 2023 Feb;21(2):237-254. doi: 10.1016/j.jtha.2022.11.011. Epub 2022 Dec 22.

PubMed [citation]
PMID:
36700498

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, SCV004031439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (2)

Description

homozygous index case: HK activity < 2%, HK antigen < 1%, prolonged aPTT two heterozygous children: HK activity 76-85%, HK Antigen 37-44%, normal aPTT

Description

This canonical splice site variant, NM_001102416.3(KNG1):c.306+2T>A, was detected in a homozygous individual deficient in high-molecular-weight kininogen (<2% HK activity, <1% HK antigen, prolonged aPTT) (PMID: 36700498) using Sanger Sequncing. Gros deletions and insertions in the corresponding area were excluded using ddPCR. The two children of the index case are heterozygous carriers of the variant and show slightly decreased HK antigen levels (37-44%). The variant has otherwise not been described in the literature and is not included in the dbSNP, which is why a very low MAF can be assumed. Predictions tools predict pathogenicity. Due to the location of the variant, a combined deficiency of HK and low-molecular-weight kininogen is likely. The base exchange affects the canonical, highly conserved donor splice site of IVS 2. Therefore, we classified this variant as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not provided1not provided

Last Updated: Sep 9, 2023