2-127428371-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000312.4(PROC):c.811C>T(p.Arg271Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: -0.920

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]

LOC105373608 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-127428371-C-T is Pathogenic according to our data. Variant chr2-127428371-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536970.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.811C>T	p.Arg271Trp	missense_variant	9/9	ENST00000234071.8
LOC105373608	XR_007087228.1	n.1041-107G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.811C>T	p.Arg271Trp	missense_variant	9/9	1	NM_000312.4	P1
PROC	ENST00000409048.1	c.913C>T	p.Arg305Trp	missense_variant	7/7	5
PROC	ENST00000402125.2	c.136C>T	p.Arg46Trp	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250824 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135670

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: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727124

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

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.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 271 of the PROC protein (p.Arg271Trp). This variant is present in population databases (rs767112991, gnomAD 0.003%). This missense change has been observed in individuals with protein C deficiency (PMID: 7482420, 18954896, 28111891; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 536970). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PROC function (PMID: 27172833). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Thrombophilia due to protein C deficiency, autosomal dominant;C2676759:Thrombophilia due to protein C deficiency, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2022

Identified in the heterozygous state in patients with deep vein thrombosis or symptomatic protein C deficiency in published literature (Miyata et al., 2009; Martos et al., 2019); Published functional studies demonstrate a severe reduction in the rate of protein C activation by thrombin-thrombomodulin (Alsultan et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as p.(R229W) using alternate nomenclature in some cases; This variant is associated with the following publications: (PMID: 27172833, 18954896, 28111891, 7482420, 31254973, 30487363) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.65
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;P
Vest4		0.45
MutPred		0.68		.;Loss of MoRF binding (P = 0.0913);
MVP		0.96
MPC		1.3
ClinPred		0.85	D
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs767112991; hg19: chr2-128185947; COSMIC: COSV52165518; COSMIC: COSV52165518;