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NM_000312.4(PROC):c.997G>A (p.Ala333Thr) AND Thrombophilia due to protein C deficiency, autosomal dominant

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 7, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003072771.2

Allele description [Variation Report for NM_000312.4(PROC):c.997G>A (p.Ala333Thr)]

NM_000312.4(PROC):c.997G>A (p.Ala333Thr)

Gene:
PROC:protein C, inactivator of coagulation factors Va and VIIIa [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q14.3
Genomic location:
Preferred name:
NM_000312.4(PROC):c.997G>A (p.Ala333Thr)
HGVS:
  • NC_000002.12:g.127428557G>A
  • NG_016323.1:g.15138G>A
  • NM_000312.4:c.997G>AMANE SELECT
  • NM_001375602.1:c.1180G>A
  • NM_001375603.1:c.1162G>A
  • NM_001375604.1:c.1060G>A
  • NM_001375605.1:c.1099G>A
  • NM_001375606.1:c.1165G>A
  • NM_001375607.1:c.1183G>A
  • NM_001375608.1:c.940G>A
  • NM_001375609.1:c.973G>A
  • NM_001375610.1:c.991G>A
  • NM_001375611.1:c.997G>A
  • NM_001375613.1:c.997G>A
  • NP_000303.1:p.Ala333Thr
  • NP_000303.1:p.Ala333Thr
  • NP_001362531.1:p.Ala394Thr
  • NP_001362532.1:p.Ala388Thr
  • NP_001362533.1:p.Ala354Thr
  • NP_001362534.1:p.Ala367Thr
  • NP_001362535.1:p.Ala389Thr
  • NP_001362536.1:p.Ala395Thr
  • NP_001362537.1:p.Ala314Thr
  • NP_001362538.1:p.Ala325Thr
  • NP_001362539.1:p.Ala331Thr
  • NP_001362540.1:p.Ala333Thr
  • NP_001362542.1:p.Ala333Thr
  • LRG_599t1:c.997G>A
  • LRG_599:g.15138G>A
  • LRG_599p1:p.Ala333Thr
  • NC_000002.11:g.128186133G>A
  • NM_000312.3:c.997G>A
Protein change:
A314T
Molecular consequence:
  • NM_000312.4:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375602.1:c.1180G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375603.1:c.1162G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375604.1:c.1060G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375605.1:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375606.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375607.1:c.1183G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375608.1:c.940G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375609.1:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375610.1:c.991G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375611.1:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001375613.1:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Thrombophilia due to protein C deficiency, autosomal dominant
Synonyms:
PROC DEFICIENCY, AUTOSOMAL DOMINANT; PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT; Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant
Identifiers:
MONDO: MONDO:0008316; MedGen: C2674321; Orphanet: 745; OMIM: 176860

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003472429Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Sep 7, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Protein C deficiency (a novel mutation: ala291Thr) with systemic lupus erythematosus leads to the deep vein thrombosis.

Su K, Zhang H, Fang W, Zhang F, Yang L, Jin Y, Wang M.

Blood Coagul Fibrinolysis. 2018 Dec;29(8):714-719. doi: 10.1097/MBC.0000000000000778.

PubMed [citation]
PMID:
30439769

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV003472429.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This missense change has been observed in individual(s) with protein C deficiency (PMID: 30439769). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 333 of the PROC protein (p.Ala333Thr). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is also known as p.Ala291Thr.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024