VCV000137635.25 - ClinVar

NM_003242.6(TGFBR2):c.571G>A (p.Val191Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003242.6(TGFBR2):c.571G>A (p.Val191Ile)

Variation ID: 137635 Accession: VCV000137635.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30671754 (GRCh38) [ NCBI UCSC ] 3: 30713246 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	May 1, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.571G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Val191Ile	missense
NM_001024847.3:c.646G>A	NP_001020018.1:p.Val216Ile	missense
NM_001407126.1:c.754G>A	NP_001394055.1:p.Val252Ile	missense
NM_001407127.1:c.679G>A	NP_001394056.1:p.Val227Ile	missense
NM_001407128.1:c.598G>A	NP_001394057.1:p.Val200Ile	missense
NM_001407129.1:c.574G>A	NP_001394058.1:p.Val192Ile	missense
NM_001407130.1:c.571G>A	NP_001394059.1:p.Val191Ile	missense
NM_001407132.1:c.466G>A	NP_001394061.1:p.Val156Ile	missense
NM_001407133.1:c.466G>A	NP_001394062.1:p.Val156Ile	missense
NM_001407134.1:c.466G>A	NP_001394063.1:p.Val156Ile	missense
NM_001407135.1:c.466G>A	NP_001394064.1:p.Val156Ile	missense
NM_001407136.1:c.466G>A	NP_001394065.1:p.Val156Ile	missense
NM_001407137.1:c.286G>A	NP_001394066.1:p.Val96Ile	missense
NM_001407138.1:c.211G>A	NP_001394067.1:p.Val71Ile	missense
NC_000003.12:g.30671754G>A
NC_000003.11:g.30713246G>A
NG_007490.1:g.70253G>A
LRG_779:g.70253G>A
LRG_779t1:c.646G>A	LRG_779p1:p.Val216Ile
LRG_779t2:c.571G>A	LRG_779p2:p.Val191Ile
	P37173:p.Val191Ile

... more HGVS ... less HGVS

Protein change

V216I, V191I, V192I, V200I, V227I, V252I, V71I, V156I, V96I

Other names

p.V191I:GTT>ATT

Canonical SPDI

NC_000003.12:30671753:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00399 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00039

Trans-Omics for Precision Medicine (TOPMed) 0.00090

The Genome Aggregation Database (gnomAD), exomes 0.00156

Exome Aggregation Consortium (ExAC) 0.00161

1000 Genomes Project 30x 0.00344

1000 Genomes Project 0.00399

Links

ClinGen: CA020776 UniProtKB: P37173#VAR_017606 dbSNP: rs56105708 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TGFBR2		No evidence available	No evidence available	GRCh38 GRCh37	1173	1200

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (1)	criteria provided, single submitter	Jul 2, 2013	RCV000125486.11
Familial thoracic aortic aneurysm and aortic dissection	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000228364.30
Loeys-Dietz syndrome 2	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000313129.13
Loeys-Dietz syndrome	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000352880.13
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Apr 7, 2023	RCV000589501.13
Colorectal cancer, hereditary nonpolyposis, type 6 Loeys-Dietz syndrome 2 Malignant tumor of esophagus	Likely benign (1)	criteria provided, single submitter	Jan 19, 2022	RCV002498604.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 16, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698198.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 12202987‚ 23228659 Comment: Variant summary: The TGFBR2 c.571G>A (p.Val191Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a … (more) Variant summary: The TGFBR2 c.571G>A (p.Val191Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 196 of 121384 control chromosomes (2 homozygotes) of all ethnicities sampled in ExAC, but was predominantly observed in the East Asian subpopulation at a frequency of 0.018741 (162/8644; 2 homozygotes). This frequency is about 5997 times the estimated maximal expected allele frequency of a pathogenic TGFBR2 variant (0.0000031), strongly suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant is referred to as a polymorphism in the literature and has been used as a SNP in an association study. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. (less)
Benign (Jul 02, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000168938.12 First in ClinVar: Jun 23, 2014 Last updated: May 29, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Feb 02, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901781.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Benign (Mar 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903047.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Apr 07, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004562170.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287924.8 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Thoracic Aortic Aneurysms and Aortic Dissections Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442845.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 12202987
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Loeys-Dietz Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442844.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 16791849
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Loeys-Dietz syndrome 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442846.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant tumor of esophagus Loeys-Dietz syndrome 2 Colorectal cancer, hereditary nonpolyposis, type 6 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807067.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Mar 21, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000319179.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001978316.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977677.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
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Comment:

Variant summary: The TGFBR2 c.571G>A (p.Val191Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 196 of 121384 control chromosomes (2 homozygotes) of all ethnicities sampled in ExAC, but was predominantly observed in the East Asian subpopulation at a frequency of 0.018741 (162/8644; 2 homozygotes). This frequency is about 5997 times the estimated maximal expected allele frequency of a pathogenic TGFBR2 variant (0.0000031), strongly suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant is referred to as a polymorphism in the literature and has been used as a SNP in an association study. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
TGFBR2 gene polymorphism is associated with ossification of the posterior longitudinal ligament.	Jekarl DW	Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia	2013	PMID: 23228659
Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.	Mátyás G	Human mutation	2006	PMID: 16791849
A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-beta1 (TGF-beta1) and its signaling pathway.	Watanabe Y	Journal of human genetics	2002	PMID: 12202987

Text-mined citations for rs56105708 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003242.6(TGFBR2):c.571G>A (p.Val191Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56105708 ...