NM_003242.6(TGFBR2):c.464C>T (p.Thr155Ile) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 11, 2017
Review status:: criteria provided, conflicting classifications

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:: RCV000154587.8

Allele description [Variation Report for NM_003242.6(TGFBR2):c.464C>T (p.Thr155Ile)]

NM_003242.6(TGFBR2):c.464C>T (p.Thr155Ile)

Gene:

TGFBR2:transforming growth factor beta receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p24.1

Genomic location:

Preferred name:

NM_003242.6(TGFBR2):c.464C>T (p.Thr155Ile)

HGVS:

NC_000003.12:g.30671647C>T
NG_007490.1:g.70146C>T
NM_001024847.3:c.539C>T
NM_001407126.1:c.647C>T
NM_001407127.1:c.572C>T
NM_001407128.1:c.491C>T
NM_001407129.1:c.467C>T
NM_001407130.1:c.464C>T
NM_001407132.1:c.359C>T
NM_001407133.1:c.359C>T
NM_001407134.1:c.359C>T
NM_001407135.1:c.359C>T
NM_001407136.1:c.359C>T
NM_001407137.1:c.179C>T
NM_001407138.1:c.104C>T
NM_003242.6:c.464C>TMANE SELECT
NP_001020018.1:p.Thr180Ile
NP_001020018.1:p.Thr180Ile
NP_001394055.1:p.Thr216Ile
NP_001394056.1:p.Thr191Ile
NP_001394057.1:p.Thr164Ile
NP_001394058.1:p.Thr156Ile
NP_001394059.1:p.Thr155Ile
NP_001394061.1:p.Thr120Ile
NP_001394062.1:p.Thr120Ile
NP_001394063.1:p.Thr120Ile
NP_001394064.1:p.Thr120Ile
NP_001394065.1:p.Thr120Ile
NP_001394066.1:p.Thr60Ile
NP_001394067.1:p.Thr35Ile
NP_003233.4:p.Thr155Ile
LRG_779t1:c.539C>T
LRG_779t2:c.464C>T
LRG_779:g.70146C>T
LRG_779p1:p.Thr180Ile
LRG_779p2:p.Thr155Ile
NC_000003.11:g.30713139C>T
NM_001024847.2:c.539C>T
NM_003242.5:c.464C>T

Protein change:

T120I

Links:

dbSNP: rs727504406

NCBI 1000 Genomes Browser:

rs727504406

Molecular consequence:

NM_001024847.3:c.539C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407126.1:c.647C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407127.1:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407128.1:c.491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407129.1:c.467C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407130.1:c.464C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407132.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407133.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407134.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407135.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407136.1:c.359C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407137.1:c.179C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407138.1:c.104C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003242.6:c.464C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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VPS54 VPS54 subunit of GARP complex [Homo sapiens]
VPS54 VPS54 subunit of GARP complex [Homo sapiens]
Gene ID:51542

Gene
Gene Links for GEO Profiles (Select 70514207) (1)
Gene
WDR11 WD repeat domain 11 [Homo sapiens]
WDR11 WD repeat domain 11 [Homo sapiens]
Gene ID:55717

Gene
Gene Links for GEO Profiles (Select 70509676) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204260	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Sep 24, 2010)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000920293	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Sep 11, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204260

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Sep 24, 2010)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000920293

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Sep 11, 2017)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204260.5

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

Description

Variant classified as Uncertain Significance - Favor Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920293.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: The TGFBR2 c.464C>T (p.Thr155Ile) variant located in the transforming growth ffactor beta receptor 2 ectodomain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome for this variant. This variant was found in 35/246096 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.001137 (35/30782). This frequency is about 364 times the estimated maximal expected allele frequency of a pathogenic TGFBR2 variant (0.0000031), suggesting this is likely a benign polymorphism found primarily in population(s) of South Asian origin. A publication, Lerner-Ellis_2014, cites the variant in one affected individual with limited information (no cosegregation data). A clinical diagnostic laboratory classified this variant as uncertain significance, however, this classification occurred prior to the availablity of gnomAD or ExAC. Therefore, the variant of interest has been classified as "benign."

#	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: Sep 29, 2024

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