VCV000927079.9 - ClinVar

NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)

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.

(6)

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.

Uncertain significance/Uncertain risk allele

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.340G>C (p.Glu114Gln)

Variation ID: 927079 Accession: VCV000927079.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30650346 (GRCh38) [ NCBI UCSC ] 3: 30691838 (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	Jun 22, 2020	May 1, 2024	Dec 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.340G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Glu114Gln	missense
NM_001024847.3:c.415G>C	NP_001020018.1:p.Glu139Gln	missense
NM_001407126.1:c.415G>C	NP_001394055.1:p.Glu139Gln	missense
NM_001407127.1:c.340G>C	NP_001394056.1:p.Glu114Gln	missense
NM_001407128.1:c.367G>C	NP_001394057.1:p.Glu123Gln	missense
NM_001407129.1:c.235G>C	NP_001394058.1:p.Glu79Gln	missense
NM_001407130.1:c.340G>C	NP_001394059.1:p.Glu114Gln	missense
NM_001407132.1:c.235G>C	NP_001394061.1:p.Glu79Gln	missense
NM_001407133.1:c.235G>C	NP_001394062.1:p.Glu79Gln	missense
NM_001407134.1:c.235G>C	NP_001394063.1:p.Glu79Gln	missense
NM_001407135.1:c.235G>C	NP_001394064.1:p.Glu79Gln	missense
NM_001407136.1:c.235G>C	NP_001394065.1:p.Glu79Gln	missense
NM_001407139.1:c.415G>C	NP_001394068.1:p.Glu139Gln	missense
NC_000003.12:g.30650346G>C
NC_000003.11:g.30691838G>C
NG_007490.1:g.48845G>C
LRG_779:g.48845G>C
LRG_779t1:c.415G>C	LRG_779p1:p.Glu139Gln
LRG_779t2:c.340G>C	LRG_779p2:p.Glu114Gln

... more HGVS ... less HGVS

Protein change

E139Q, E114Q, E123Q, E79Q

Other names

Canonical SPDI

NC_000003.12:30650345:G:C

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00005

Links

dbSNP: rs771551560 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.
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 23, 2023	RCV001190092.8
Colorectal cancer, hereditary nonpolyposis, type 6 Loeys-Dietz syndrome 2 Malignant tumor of esophagus	Uncertain significance (1)	criteria provided, single submitter	Aug 17, 2021	RCV002491568.1
Diabetic retinopathy	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV004033399.1
Loeys-Dietz syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2023	RCV004010407.2

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.
Uncertain significance (Aug 17, 2021)	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: SCV002778437.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 23, 2023)	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: SCV004279061.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 114 of the TGFBR2 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 114 of the TGFBR2 protein (p.Glu114Gln). This variant is present in population databases (rs771551560, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 927079). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR2 protein function with a negative predictive value of 95%. 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. (less)
Uncertain significance (Nov 01, 2023)	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: SCV001357507.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 18, 2023)	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: SCV003998020.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.340G>C (p.E114Q) alteration is located in exon 3 (coding exon 3) of the TGFBR2 gene. This alteration results from a G to C substitution … (more) The c.340G>C (p.E114Q) alteration is located in exon 3 (coding exon 3) of the TGFBR2 gene. This alteration results from a G to C substitution at nucleotide position 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain Significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Loeys-Dietz syndrome 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004839159.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 3
Uncertain risk allele (-)	criteria provided, single submitter (K And H Uppaluri Personalized Medicine Clinic Variant Classification And Assertion Criteria Updated V 2) Method: research	Diabetic retinopathy Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV005016457.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 30222965‚ 28162229‚ 34572573 Comment: Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for … (more) Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs771551560 with diabetic retinopathy. (less)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 114 of the TGFBR2 protein (p.Glu114Gln). This variant is present in population databases (rs771551560, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 927079). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR2 protein function with a negative predictive value of 95%. 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.

Comment:

This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The c.340G>C (p.E114Q) alteration is located in exon 3 (coding exon 3) of the TGFBR2 gene. This alteration results from a G to C substitution at nucleotide position 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs771551560 with diabetic retinopathy.

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:

This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain.	Schlecht A	Biomolecules	2021	PMID: 34572573
Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy.	Platania CBM	Biochemical pharmacology	2018	PMID: 30222965
The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels.	Dagher Z	The American journal of pathology	2017	PMID: 28162229

Text-mined citations for rs771551560 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs771551560 ...