Submissions for variant NM_000312.4(PROC):c.925G>A (p.Ala309Thr)

gnomAD frequency: 0.00002  dbSNP: rs121918146

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689442	SCV000817093	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 309 of the PROC protein (p.Ala309Thr). This variant is present in population databases (rs121918146, gnomAD 0.002%). This missense change has been observed in individuals with protein C deficiency (PMID: 1347608, 17152060, 19535131, 28607330). It has also been observed to segregate with disease in related individuals. This variant is also known as Ala267Thr. ClinVar contains an entry for this variant (Variation ID: 662). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROC function (PMID: 20815936, 21901152). For these reasons, this variant has been classified as Pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000689442	SCV002500901	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003985071	SCV004801534	pathogenic	Hereditary thrombophilia due to congenital protein C deficiency	2017-06-26	criteria provided, single submitter	clinical testing	The PROC c.925G>A (p.Ala309Thr) variant, also known as p.Ala267Thr, has been reported in at least four studies in 13 individuals with protein C deficiency including six individuals in a homozygous state (of which five are related) and one individual in a compound heterozygous state (Conard et al. 1992; Gandrille et al. 1995; Loop et al. 2004; Tjeldhorn et al. 2010a). In the family reported by Tjeldhorn et al. (2010a), the patient developed deep vein thrombosis in her leg at the age of 16 and skin necrosis after warfarin use, while her four family members homozygous for the variant did not have evidence of venous thrombosis but did have significantly reduced protein C activity and antigen in plasma. Several reported patients experienced episodes of skin necrosis following treatments with anticoagulants (Conard et al. 1992; Loop et al. 2004; Tjeldhorn et al. 2010a). The p.Ala309Thr variant was reported in a heterozygous state in six individuals from three families, including four individuals with no overt clinical symptoms but reduced protein C activity and one individual described as symptomatic but with no further clinical details provided. Reported individuals heterozygous for the p.Ala309Thr variant had a protein C activity ranging from 45 to 63 percent of normal, while individuals homozygous or compound heterozygous for the variant displayed more significant reduction, as low a three percent (Loop et al. 2004; Tjeldhorn et al. 2010a). Expression analysis in CHO and Huh7 cells found pAla309Thr demonstrated reduced intracellular levels, impaired secretion, and altered localization with inefficient transport compared to WT (Tjeldhorn et al. 2010b). A subsequent study by Tjeldhorn et al. found p.Ala309Thr to be associated with increased ER stress and unfolded protein response (UPR), which were associated with increased apoptotic activity in cells (Tjeldhorn et al. 2011). Using 4-phenylbutyrate (PBA) on CHO cells expressing p.Ala309Thr secretion was improved, localization was altered to the cytoplasm using the GRASP55 pathway (Chollet et al. 2015). The p.Ala309Thr variant was absent from 140 control chromosomes and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Ala309Thr variant is classified as pathogenic for protein C deficiency.
Mayo Clinic Laboratories, Mayo Clinic	RCV004791187	SCV005413504	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	PP1_strong, PP5, PM1_supporting, PM2_moderate, PM3, PS3, PS4_moderate
OMIM	RCV000000697	SCV000020847	pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	1992-03-21	no assertion criteria provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000689442	SCV004041720	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2023-10-09	no assertion criteria provided	clinical testing