rs121918153

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000312.4(PROC):c.659G>A(p.Arg220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

PROC
NM_000312.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.0320

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-127426207-C-T is described in Lovd as [Likely_pathogenic].

PP5

Variant 2-127426208-G-A is Pathogenic according to our data. Variant chr2-127426208-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127426208-G-A 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.659G>A	p.Arg220Gln	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.659G>A	p.Arg220Gln	missense_variant	Exon 7 of 9	1	NM_000312.4	ENSP00000234071.4		P04070-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251324

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:4

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PROC c.659G>A (p.Arg220Gln) variant has been reported in six studies in which it is found in a total of 30 individuals with protein C deficiency, all in a heterozygous state (Gandrille et al. 1992; Grundy et al. 1992; Poort et al. 1993; Millar et al. 1995; Soria et al. 1996; Couture et al. 1998). The p.Arg220Gln variant was absent from 50 ethnically matched controls and is reported at a frequency of 0.00067 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg220Gln is classified as pathogenic for protein C deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PROC c.659G>A (p.Arg220Gln) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251324 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.659G>A has been reported in the literature in multiple individuals affected with Thrombophilia Due To Protein C Deficiency, Autosomal Dominant (Grundy_1992, Miyata_2009, Martos_2019). These data indicate that the variant is very likely to 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: 1511989, 31254973, 18954896, 1868249, 32309994). ClinVar contains an entry for this variant (Variation ID: 669). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 18, 2025

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 glutamine, which is neutral and polar, at codon 220 of the PROC protein (p.Arg220Gln). This variant is present in population databases (rs121918153, gnomAD 0.06%). This missense change has been observed in individuals with protein C deficiency (PMID: 1301954, 1301959, 1511989, 7605880, 8499565, 18954896, 31254973). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg178Gln. ClinVar contains an entry for this variant (Variation ID: 669). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PROC protein function with a negative predictive value of 80%. This variant disrupts the p.Arg220 amino acid residue in PROC. Other variant(s) that disrupt this residue have been observed in individuals with PROC-related conditions (PMID: 1868249, 2602169, 7605880, 21621249), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Nov 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PM1, PM2_moderate, PS3_moderate, PS4 -

Jun 04, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Reduced protein C activity

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive

Pathogenic:1

Dec 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Uncertain

0.53

D;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.81

L;.

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.42

N;N

REVEL

Uncertain

0.52

Sift4G

Benign

0.31

T;T

Polyphen

0.36

B;B

Vest4

0.061

MVP

0.77

MPC

0.52

ClinPred

0.014

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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