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

dbSNP: rs199469469

Total submissions: 4

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 due to protein C deficiency, autosomal dominant	2016-03-18	criteria provided, single submitter	reference population
Illumina Laboratory Services, Illumina	RCV000288890	SCV000416365	pathogenic	Thrombophilia 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 due to protein C deficiency, autosomal dominant	2021-07-13	criteria provided, single submitter	clinical testing	This variant, c.577_579del, results in the deletion of 1 amino acid(s) 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%). This variant has been observed in individual(s) with protein C deficiency as well as unaffected control individuals from East Asian populations. 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). However, this needs further validation in a larger study (PMID: 9840027, 19822351, 21486865, 22817391, 23332921, 24028705, 24162787, 26250584). This variant is also known as Lys150del or c.574_576del (p.Lys192del). ClinVar contains an entry for this variant (Variation ID: 225448). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PROC protein function (PMID: 19822351, 21486865, 22817391, 23389250, 24028705, 24162787, 26250584). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479063	SCV004223000	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: PROC c.577_579delAAG (p.Lys193del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0007 in 251380 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although this frequency is not suggestive of a variant associated with highly penetrant Mendelian disease. c.577_579delAAG has been reported in the literature as a risk factor for venous thrombosis and ischemic stroke, without a clear pattern of Mendelian inheritance, predominantly in individuals of East Asian descent (e.g., Tang_2012, Lu_2013). Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a moderate reduction in anticoagulant activity relative to wild-type as well as a distinct transcriptional profile in HEK 293T cells (e.g., Tang_2012, Ding_2013, Lin_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23389250, 33896796, 22976599, 22817391). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as uncertain significance (n = 2) and pathogenic (n = 1). Based on the evidence outlined above, the variant likely represents a risk allele for venous thrombosis and ischemic stroke and was therefore classified as VUS-possibly pathogenic.