ClinVar Miner

Submissions for variant NM_000312.4(PROC):c.400+5G>C

gnomAD frequency: 0.00001  dbSNP: rs199469478
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001270878 SCV001451655 uncertain significance Thrombophilia due to protein C deficiency, autosomal dominant 2019-02-12 criteria provided, single submitter clinical testing The PROC c.400+5G>C variant is a splice region variant. This variant has been identified in a single heterozygous individual with protein C deficiency with the level of protein C at 58% of normal levels (Bruwer et al. 2016). The variant is not found in the Genome Aggregation Database in a region of good sequencing coverage so the variant is presumed to be rare. Based on the limited evidence, the c.400+5G>C variant is classified as a variant of uncertain significance for protein C deficiency.
Invitae RCV001270878 SCV002201414 pathogenic Thrombophilia due to protein C deficiency, autosomal dominant 2023-09-08 criteria provided, single submitter clinical testing This variant disrupts the c.400+5G nucleotide in the PROC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1868249, 31254973). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change falls in intron 5 of the PROC gene. It does not directly change the encoded amino acid sequence of the PROC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199469478, gnomAD 0.006%). This variant has been observed in individual(s) with protein C deficiency (PMID: 1868249, 2783855; 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 3222 G>C. ClinVar contains an entry for this variant (Variation ID: 989365).
Mayo Clinic Laboratories, Mayo Clinic RCV003481043 SCV004224954 uncertain significance not provided 2022-07-11 criteria provided, single submitter clinical testing PP3, PM2

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