NM_000313.4(PROS1):c.797A>G (p.Tyr266Cys) AND Thrombophilia due to protein S deficiency, autosomal recessive

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 20, 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:: RCV002651717.2

Allele description [Variation Report for NM_000313.4(PROS1):c.797A>G (p.Tyr266Cys)]

NM_000313.4(PROS1):c.797A>G (p.Tyr266Cys)

Gene:

PROS1:protein S [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q11.1

Genomic location:

Preferred name:

NM_000313.4(PROS1):c.797A>G (p.Tyr266Cys)

HGVS:

NC_000003.12:g.93898500T>C
NG_009813.1:g.80591A>G
NM_000313.4:c.797A>GMANE SELECT
NM_001314077.2:c.893A>G
NP_000304.2:p.Tyr266Cys
NP_000304.2:p.Tyr266Cys
NP_001301006.1:p.Tyr298Cys
NP_001301006.1:p.Tyr298Cys
LRG_572t1:c.797A>G
LRG_572t2:c.893A>G
LRG_572:g.80591A>G
LRG_572p1:p.Tyr266Cys
LRG_572p2:p.Tyr298Cys
NC_000003.11:g.93617344T>C
NM_000313.3:c.797A>G
NM_001314077.1:c.893A>G

Protein change:

Y266C

Molecular consequence:

NM_000313.4:c.797A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001314077.2:c.893A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Thrombophilia due to protein S deficiency, autosomal recessive (THPH6)
Identifiers:: MONDO: MONDO:0013791; MedGen: C3281092; Orphanet: 743; OMIM: 614514

Recent activity

Clear Turn Off Turn On

pyridoxal phosphate phosphatase PHOSPHO2 [Homo sapiens]
pyridoxal phosphate phosphatase PHOSPHO2 [Homo sapiens]
gi|313151197|ref|NP_001186217.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003525256	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15712227, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003525256

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 20, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study.

Biguzzi E, Razzari C, Lane DA, Castaman G, Cappellari A, Bucciarelli P, Fontana G, Margaglione M, D'Andrea G, Simmonds RE, Rezende SM, Preston R, Prisco D, Faioni EM; Protein S Italian Team..

Hum Mutat. 2005 Mar;25(3):259-69.

PubMed [citation]

PMID:: 15712227

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, SCV003525256.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROS1 function (PMID: 15712227). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 266 of the PROS1 protein (p.Tyr266Cys). This variant is present in population databases (rs777616039, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of autosomal dominant PROS1-related conditions (PMID: 15712227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15").

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

ClinVar

Relating variation to medicine