rs121918146

Positions:

chr2-127428485-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000312.4(PROC):c.925G>A(p.Ala309Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,974 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A309A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PROC
NM_000312.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.85

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 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000312.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 2-127428485-G-A is Pathogenic according to our data. Variant chr2-127428485-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.925G>A	p.Ala309Thr	missense_variant	9/9	ENST00000234071.8
LOC105373608	XR_007087228.1 linkuse as main transcript	n.1041-221C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.925G>A	p.Ala309Thr	missense_variant	9/9	1	NM_000312.4	P1	P04070-1
PROC	ENST00000409048.1 linkuse as main transcript	c.1027G>A	p.Ala343Thr	missense_variant	7/7	5
PROC	ENST00000402125.2 linkuse as main transcript	c.250G>A	p.Ala84Thr	missense_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251356

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 06, 2022	This variant is also known as Ala267Thr. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PROC function (PMID: 20815936, 21901152). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 662). This missense change has been observed in individuals with protein C deficiency (PMID: 1347608, 17152060, 19535131, 28607330). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918146, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 309 of the PROC protein (p.Ala309Thr). -

Hereditary thrombophilia due to congenital protein C deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 26, 2017

The PROC c.925G>A (p.Ala309Thr) variant, also known as p.Ala267Thr, has been reported in at least four studies in 13 individuals with protein C deficiency including six individuals in a homozygous state (of which five are related) and one individual in a compound heterozygous state (Conard et al. 1992; Gandrille et al. 1995; Loop et al. 2004; Tjeldhorn et al. 2010a). In the family reported by Tjeldhorn et al. (2010a), the patient developed deep vein thrombosis in her leg at the age of 16 and skin necrosis after warfarin use, while her four family members homozygous for the variant did not have evidence of venous thrombosis but did have significantly reduced protein C activity and antigen in plasma. Several reported patients experienced episodes of skin necrosis following treatments with anticoagulants (Conard et al. 1992; Loop et al. 2004; Tjeldhorn et al. 2010a). The p.Ala309Thr variant was reported in a heterozygous state in six individuals from three families, including four individuals with no overt clinical symptoms but reduced protein C activity and one individual described as symptomatic but with no further clinical details provided. Reported individuals heterozygous for the p.Ala309Thr variant had a protein C activity ranging from 45 to 63 percent of normal, while individuals homozygous or compound heterozygous for the variant displayed more significant reduction, as low a three percent (Loop et al. 2004; Tjeldhorn et al. 2010a). Expression analysis in CHO and Huh7 cells found pAla309Thr demonstrated reduced intracellular levels, impaired secretion, and altered localization with inefficient transport compared to WT (Tjeldhorn et al. 2010b). A subsequent study by Tjeldhorn et al. found p.Ala309Thr to be associated with increased ER stress and unfolded protein response (UPR), which were associated with increased apoptotic activity in cells (Tjeldhorn et al. 2011). Using 4-phenylbutyrate (PBA) on CHO cells expressing p.Ala309Thr secretion was improved, localization was altered to the cytoplasm using the GRASP55 pathway (Chollet et al. 2015). The p.Ala309Thr variant was absent from 140 control chromosomes and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Ala309Thr variant is classified as pathogenic for protein C deficiency. -

Thrombophilia due to protein C deficiency, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 21, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.68

T;T

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.9

M;.

MutationTaster

Benign

6.4e-9

A;A;A;A

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.58

Sift4G

Benign

0.24

T;T

Polyphen

0.90

P;P

Vest4

0.20

MutPred

0.81

.;Gain of glycosylation at A343 (P = 0.0443);

MVP

0.94

MPC

0.59

ClinPred

0.53

GERP RS

3.4

Varity_R

0.63

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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