ClinVar Miner

Submissions for variant NM_000312.4(PROC):c.1019C>T (p.Thr340Met)

gnomAD frequency: 0.00001  dbSNP: rs766261022
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000702555 SCV000831413 pathogenic Thrombophilia due to protein C deficiency, autosomal dominant 2023-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 340 of the PROC protein (p.Thr340Met). This variant is present in population databases (rs766261022, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of protein C deficiency (PMID: 7670104, 8292730, 8704244, 31254973; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as T298M. ClinVar contains an entry for this variant (Variation ID: 579309). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROC protein function. 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 RCV002245610 SCV002515557 likely pathogenic Reduced protein C activity no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004754536 SCV005360132 pathogenic PROC-related disorder 2024-04-11 no assertion criteria provided clinical testing The PROC c.1019C>T variant is predicted to result in the amino acid substitution p.Thr340Met. This variant, previously reported as p.Thr298Met using legacy nomenclature, has been found in individuals with Protein C deficiency (Tsay et al. 1993. PubMed ID: 8292730; Douglas et al. 2010. PubMed ID: 21045961; Martos et al. 2019. PubMed ID: 31254973). Two infants with purpura fulminans have been reported with one infant being homozygous for the c.1019C>T variant and another infant having a second pathogenic variant in trans (Brenner et al. 1996. PubMed ID: 8704244; Douglas et al. 2010. PubMed ID: 21045961). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

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