rs199469469

chr2-127426120-GAGA-Gchr2-127426120-GAGA-GAGAAGA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PM4_Supporting

The NM_000312.4(PROC):c.577_579del(p.Lys193del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,614,122 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

PROC
NM_000312.4 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.48

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 Uncertain_significance. Variant got 3 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, 5 uncertain in NM_000312.4

PM4

Nonframeshift variant in NON repetitive region in NM_000312.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4 linkuse as main transcript	c.577_579del	p.Lys193del	inframe_deletion	7/9	ENST00000234071.8
LOC105373608	XR_007087228.1 linkuse as main transcript	n.3182_3184del		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8 linkuse as main transcript	c.577_579del	p.Lys193del	inframe_deletion	7/9	1	NM_000312.4	P1	P04070-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152202

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:

0.00732

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

GnomAD3 exomes

AF:

0.000704

AC:

177

AN:

251380

Hom.:

AF XY:

0.000603

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00957

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1461802

Hom.:

AF XY:

0.000168

AC XY:

122

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00680

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000249

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00734

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000252

Hom.:

Bravo

AF:

0.000419

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 13, 2021	This variant, c.577_579del, results in the deletion of 1 amino acid(s) of the PROC protein (p.Lys193del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs569796900, ExAC 0.9%). This variant has been observed in individual(s) with protein C deficiency as well as unaffected control individuals from East Asian populations. In a small case-control study including 1304 cases and 1334 controls from Chinese population, this variant was significantly associated with venous thrombosis (OR: 2.84, 95% CI 1.88-4.29). However, this needs further validation in a larger study (PMID: 9840027, 19822351, 21486865, 22817391, 23332921, 24028705, 24162787, 26250584). This variant is also known as Lys150del or c.574_576del (p.Lys192del). ClinVar contains an entry for this variant (Variation ID: 225448). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PROC protein function (PMID: 19822351, 21486865, 22817391, 23389250, 24028705, 24162787, 26250584). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PROC c.577_579delAAG (p.Lys193del) variant, which has several alternative names, has been well-described in the literature. The p.Lys193del variant is reported in at least seven studies in individuals with protein C deficiency and thrombotic disease in which it was found in 162 individuals, including two in a homozygous state (Miyata et al. 1998; Kinoshita et al. 2005; Tang et al. 2012; Tang et al. 2013; Iijima et al. 2010; Gu et al. 2014; Kim et al. 2014). In the same studies, the variant was detected in 69 out of 2,887 controls and is reported at a frequency of 0.00925 in the East Asian population of the Exome Aggregation Consortium. Tang et al. (2013) reported the frequency of the variant to be significantly higher in individuals with protein C deficiency and thrombotic disease compared to healthy individuals with an odds ratio of 2.84. The Lys193 residue is conserved among mammals. Protein C anticoagulant and amidolytic activities in individuals carrying the p.Lys193del variant in a heterozygous state can range from being only slightly reduced to being nearly normal (Iijima et al. 2010, Tang et al. 2012). Given the high prevalence of the variant in controls, the p.Lys193del variant is considered to be associated with incomplete penetrance. Not all individuals who carry this variant will demonstrate a reduction in levels of protein C activity. However, based on the strong association with disease and the combined evidence from the literature, the p.Lys193del variant 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 03, 2023

Variant summary: PROC c.577_579delAAG (p.Lys193del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0007 in 251380 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although this frequency is not suggestive of a variant associated with highly penetrant Mendelian disease. c.577_579delAAG has been reported in the literature as a risk factor for venous thrombosis and ischemic stroke, without a clear pattern of Mendelian inheritance, predominantly in individuals of East Asian descent (e.g., Tang_2012, Lu_2013). Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a moderate reduction in anticoagulant activity relative to wild-type as well as a distinct transcriptional profile in HEK 293T cells (e.g., Tang_2012, Ding_2013, Lin_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23389250, 33896796, 22976599, 22817391). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as uncertain significance (n = 2) and pathogenic (n = 1). Based on the evidence outlined above, the variant likely represents a risk allele for venous thrombosis and ischemic stroke and was therefore classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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