Submissions for variant NM_000312.4(PROC):c.703A>C (p.Lys235Gln)

gnomAD frequency: 0.00015  dbSNP: rs370086431

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002221176	SCV002498584	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2020-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002246694	SCV002519217	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002246694	SCV003934443	uncertain significance	not specified	2023-05-11	criteria provided, single submitter	clinical testing	Variant summary: PROC c.703A>C (p.Lys235Gln) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251262 control chromosomes (gnomAD). c.703A>C has been reported in the literature in individuals affected with Protein C Deficiency (examples: Alhenc-Gelas_2000 and Martos_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Thrombophilia Due To Protein C Deficiency, Autosomal Dominant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10669160, 31254973). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic and as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002221176	SCV004247284	uncertain significance	Thrombophilia due to protein C deficiency, autosomal dominant	2023-04-25	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PROC protein function. ClinVar contains an entry for this variant (Variation ID: 1676213). This missense change has been observed in individual(s) with clinical features of PROC-related conditions (PMID: 10669160, 31254973, 34355501). This variant is present in population databases (rs370086431, gnomAD 0.05%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 235 of the PROC protein (p.Lys235Gln).
Baylor Genetics	RCV004558904	SCV005049494	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	2024-03-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004793740	SCV005412877	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	PP5, PM1_supporting, PM2