2-127426207-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000312.4(PROC):c.658C>T(p.Arg220Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PROC
NM_000312.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.259

Variant links:

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

PROC links:

LOC105373608 (HGNC:):

LOC105373608 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-127426208-G-A is described in Lovd as [Likely_pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-127426207-C-T is Pathogenic according to our data. Variant chr2-127426207-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127426207-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 7 of 9	ENST00000234071.8	NP_000303.1	P04070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8 link	c.658C>T	p.Arg220Trp	missense_variant	Exon 7 of 9	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:3

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

We found a four-generation Chinese pedigree with hereditary thrombophilia, comprising seven affected individuals presenting recurrent thrombotic events involving both venous and arterial systems. Clinical manifestations included pulmonary embolism, chronic pulmonary hypertension, lower extremity deep vein thrombosis, and arterial thrombosis. Genetic analysis via next-generation sequencing (NGS) followed by Sanger validation identified a heterozygous missense mutation in the PROC gene (NM_000312.4: c.658C>T [p.Arg220Trp]) segregating with the phenotype in the proband and all symptomatic family members. Western blot and ELISA demonstrated increased intracellular PC expression and elevated secretion levels in culture supernatants compared to wild-type (WT) controls. In contrast, chromogenic assays assessing plasma anticoagulant activity showed significantly reduced activated protein C (APC) activity in mutation carriers, consistent with impaired functional capacity despite heightened protein abundance. These results indicate that the mutation will cause high secretion-low expression of APC. -

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PROC protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with protein C deficiency (PMID: 1511989, 1868249, 25393254, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg178Trp. ClinVar contains an entry for this variant (Variation ID: 668). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 25, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PROC-related disorder

Pathogenic:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROC c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant, described as R178W using legacy nomenclature, segregated with autosomal dominant protein C deficiency in two unrelated families (Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989), although some individuals were symptomatic while others were asymptomatic. This variant has also been observed in the compound heterozygous state in an individual with severe venous thromboembolic disease (Wu et al. 2014. PubMed ID: 25393254) and has been reported along with a second variant in this gene in one individual with protein C deficiency (Tang. et al. 2022. PubMed ID: 35026611). Alternative missense changes at the same amino acid position (i.e. p.Arg220Gly and p.Arg220Gln) have been reported in patients with protein C deficiency (David et al. 2011. PubMed ID: 21621249; Reitsma et al. 1991. PubMed ID: 1868249; Grundy et al. 1992. PubMed ID: 1511989). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.18

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.57

Sift4G

Benign

0.13

T;T

Polyphen

0.38

B;B

Vest4

0.14

MutPred

0.74

.;Loss of disorder (P = 0.0124);

MVP

0.88

MPC

0.48

ClinPred

0.13

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -2

DS_DL_spliceai

0.79

Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over