rs199469469

Variant names:

• chr2-127426120-GAGA-G
• rs199469469
• NM_000312.4:c.577_579delAAG

Your query was ambiguous. Multiple possible variants found:

• chr2-127426120-GAGA-G
• chr2-127426120-GAGA-GAGAAGA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4_Supporting PP5 BS1_Supporting BS2

The NM_000312.4(PROC):​c.577_579delAAG​(p.Lys193del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.48
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• hereditary thrombophilia due to congenital protein C deficiency

  Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• thrombophilia due to protein C deficiency, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• thrombophilia due to protein C deficiency, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

LOC105373608 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000312.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-127426120-GAGA-G is Pathogenic according to our data. Variant chr2-127426120-GAGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225448.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000249 (38/152320) while in subpopulation EAS AF = 0.00734 (38/5178). AF 95% confidence interval is 0.0055. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.577_579delAAG	p.Lys193del	conservative_inframe_deletion	Exon 7 of 9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.577_579delAAG	p.Lys193del	conservative_inframe_deletion	Exon 7 of 9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152202 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000704 AC: 177 AN: 251380 AF XY: 0.000603

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 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.: 2 AF XY: 0.000168 AC XY: 122 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00680 AC: 270 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

Nov 03, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.5
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199469469; hg19: chr2-128183696;