Submissions for variant NM_000312.4(PROC):c.1201G>A (p.Asp401Asn)

gnomAD frequency: 0.00001  dbSNP: rs142742242

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851669	SCV000899453	likely pathogenic	Reduced protein C activity	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148740	SCV004293375	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2023-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 401 of the PROC protein (p.Asp401Asn). This variant is present in population databases (rs142742242, gnomAD 0.009%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7865674). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp359Asn. ClinVar contains an entry for this variant (Variation ID: 161334). 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 expected to disrupt PROC protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004658975	SCV005153054	pathogenic	Inborn genetic diseases	2024-05-06	criteria provided, single submitter	clinical testing	The c.1201G>A (p.D401N) alteration is located in exon 9 (coding exon 8) of the PROC gene. This alteration results from a G to A substitution at nucleotide position 1201, causing the aspartic acid (D) at amino acid position 401 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/249342) total alleles studied. The highest observed frequency was 0.009% (3/34540) of Latino alleles. This variant was reported heterozygous in multiple individuals with features consistent with thrombophilia related to protein C deficiency (Zheng, 1994; Rovida, 2007; Douglas, 2010; Piccini, 2014). Additionally, this variant has been identified in the homozygous state and/or in conjunction with another PROC variant in individuals with features consistent with thrombophilia related to protein C deficiency (Douglas, 2010; Piccini, 2014). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
CSER _CC_NCGL, University of Washington	RCV000148740	SCV000190477	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant	2014-06-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000148740	SCV000484929	pathogenic	Thrombophilia due to protein C deficiency, autosomal dominant		no assertion criteria provided	clinical testing