ClinVar Miner

Submissions for variant NM_000312.4(PROC):c.574AAG[1] (p.Lys193del) (rs199469469)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000288890 SCV000267464 uncertain significance Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant 2016-03-18 criteria provided, single submitter reference population
Illumina Clinical Services Laboratory,Illumina RCV000288890 SCV000416365 pathogenic Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant 2017-04-27 criteria provided, single submitter clinical testing The PROC c.577_579delAAG (p.Lys193del) variant, which has several alternative names, has been well-described in the literature. The p.Lys193del variant is reported in at least seven studies in individuals with protein C deficiency and thrombotic disease in which it was found in 162 individuals, including two in a homozygous state (Miyata et al. 1998; Kinoshita et al. 2005; Tang et al. 2012; Tang et al. 2013; Iijima et al. 2010; Gu et al. 2014; Kim et al. 2014). In the same studies, the variant was detected in 69 out of 2,887 controls and is reported at a frequency of 0.00925 in the East Asian population of the Exome Aggregation Consortium. Tang et al. (2013) reported the frequency of the variant to be significantly higher in individuals with protein C deficiency and thrombotic disease compared to healthy individuals with an odds ratio of 2.84. The Lys193 residue is conserved among mammals. Protein C anticoagulant and amidolytic activities in individuals carrying the p.Lys193del variant in a heterozygous state can range from being only slightly reduced to being nearly normal (Iijima et al. 2010, Tang et al. 2012). Given the high prevalence of the variant in controls, the p.Lys193del variant is considered to be associated with incomplete penetrance. Not all individuals who carry this variant will demonstrate a reduction in levels of protein C activity. However, based on the strong association with disease and the combined evidence from the literature, the p.Lys193del variant is classified as pathogenic for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000288890 SCV001419976 uncertain significance Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant 2019-12-07 criteria provided, single submitter clinical testing This variant, c.577_579delAAG, results in the deletion of 1 amino acid of the PROC protein (p.Lys193del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs569796900, ExAC 0.9%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals with protein C deficiency as well as unaffected control individuals from East Asian populations (PMID: 9840027, 19822351, 24162787, 21486865, 26250584, 24028705). In a small case-control study including 1304 cases and 1334 controls from Chinese population, this variant was significantly associated with venous thrombosis (OR: 2.84, 95% CI 1.88-4.29) (PMID: 23332921, 22817391). However, this needs further validation in a larger study. This variant is also known as Lys150del or c.574_576del (p.Lys192del) in the literature. ClinVar contains an entry for this variant (Variation ID: 225448). This variant show reduced protein C level or anticoagulant activity with a broad activity range (~20-70%) in patient-derived plasma (PMID: 24162787, 19822351, 21486865, 26250584, 24028705). In addition, experimental studies have shown that this missense affects anticoagulant activity in vitro (PMID: 22817391, 23389250). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001310433 SCV001500226 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing

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