Submissions for variant NM_000312.4(PROC):c.127G>A (p.Ala43Thr)

gnomAD frequency: 0.00004  dbSNP: rs767626189

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001801321	SCV002047530	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2021-12-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416461	SCV004107110	uncertain significance	PROC-related disorder	2023-04-11	criteria provided, single submitter	clinical testing	The PROC c.127G>A variant is predicted to result in the amino acid substitution p.Ala43Thr. This variant has been reported in the heterozygous state in individuals with type II protein C deficiency and thromboembolic events, however it was also reported in family members who did not have thromboembolic events (Referred to as Ala+t to Thr and G1390 to A, Dodojacek et al. 2000. PubMed ID: 11053623; Table S2, Martos et al. 2019. PubMed ID: 31254973; Table S2, Alhenc-Gelas et al. 2020. PubMed ID: 32717757; Seidel et al. 2020. PubMed ID: 32309994). Of note, one individual noted above also carried the factor V Leiden variant (Seidel et al. 2020. PubMed ID: 32309994). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-128178915-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690134	SCV005184438	uncertain significance	not specified	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: PROC c.127G>A (p.Ala43Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251124 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PROC causing Thrombophilia Due To Protein C Deficiency, Autosomal Dominant, allowing no conclusion about variant significance. c.127G>A has been reported in the literature in individuals affected with Thrombophilia Due To Protein C Deficiency, Autosomal Dominant (Dodojacek_2000, Martos_2019, Seidel_2020). These data indicate that the variant may be associated with disease. 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: 11053623, 31254973, 32309994). ClinVar contains an entry for this variant (Variation ID: 1330289). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.