VCV000213913.24 - ClinVar

NM_003242.6(TGFBR2):c.94+16293C>A

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Uncertain risk allele(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003242.6(TGFBR2):c.94+16293C>A

Variation ID: 213913 Accession: VCV000213913.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30623270 (GRCh38) [ NCBI UCSC ] 3: 30664762 (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	Dec 19, 2017	Sep 16, 2024	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.94+16293C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001024847.3:c.166C>A	NP_001020018.1:p.His56Asn	missense
NM_001407126.1:c.166C>A	NP_001394055.1:p.His56Asn	missense
NM_001407128.1:c.118C>A	NP_001394057.1:p.His40Asn	missense
NM_001407133.1:c.-118C>A
NM_001407136.1:c.-128C>A
NM_001407137.1:c.166C>A	NP_001394066.1:p.His56Asn	missense
NM_001407139.1:c.166C>A	NP_001394068.1:p.His56Asn	missense
NC_000003.12:g.30623270C>A
NC_000003.11:g.30664762C>A
NG_007490.1:g.21769C>A
LRG_779:g.21769C>A
LRG_779t1:c.166C>A	LRG_779p1:p.His56Asn
LRG_779t2:c.94+16293C>A

... more HGVS ... less HGVS

Protein change

H56N, H40N

Other names

Canonical SPDI

NC_000003.12:30623269:C: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA050443 dbSNP: rs138262219 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 provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 23, 2024	RCV000196914.23
Colorectal cancer, hereditary nonpolyposis, type 6 Loeys-Dietz syndrome 2 Malignant tumor of esophagus	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000765719.10
Familial thoracic aortic aneurysm and aortic dissection	Likely benign (1)	criteria provided, single submitter	Nov 9, 2022	RCV001088557.15
Diabetic retinopathy	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV004020378.1

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 (Feb 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000250922.17 First in ClinVar: Oct 11, 2015 Last updated: Sep 16, 2024	Comment: At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis is … (more) At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 23099432) (less)
Uncertain significance (Oct 31, 2018)	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: SCV000897086.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Oct 07, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049249.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The TGFBR2 c.166C>A; p.His56Asn variant (rs138262219), has been reported in the literature in one Ashkenazi Jewish patient with thoracic aortopathy and in his affected son. … (more) The TGFBR2 c.166C>A; p.His56Asn variant (rs138262219), has been reported in the literature in one Ashkenazi Jewish patient with thoracic aortopathy and in his affected son. However, functional tests conducted in fibroblasts from this individual and in a rat cell culture model demonstrated conflicting effects of this variant on downstream TGFBR2 signaling and functioning (Bee 2012). This variant is reported in the ClinVar database (Variation ID: 213913) and is found in the Ashkenazi Jewish population with an allele frequency of 0.1 % (11/10,068 alleles) in the Genome Aggregation Database. The histidine at codon 56 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of the p.His56Asn variant is uncertain at this time. REFERENCES Bee KJ et al CJ. TGFBRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor B2 signal transduction. Circ Cardiovasc Genet. 2012 Dec;5(6):621-9. PMID: 23099432. (less)
Likely benign (Nov 09, 2022)	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: SCV001131854.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
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: SCV005016410.1 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 rs138262219 with diabetic retinopathy. (less)

Comment:

At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 23099432)

Comment:

The TGFBR2 c.166C>A; p.His56Asn variant (rs138262219), has been reported in the literature in one Ashkenazi Jewish patient with thoracic aortopathy and in his affected son. However, functional tests conducted in fibroblasts from this individual and in a rat cell culture model demonstrated conflicting effects of this variant on downstream TGFBR2 signaling and functioning (Bee 2012). This variant is reported in the ClinVar database (Variation ID: 213913) and is found in the Ashkenazi Jewish population with an allele frequency of 0.1 % (11/10,068 alleles) in the Genome Aggregation Database. The histidine at codon 56 is weakly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of the p.His56Asn variant is uncertain at this time. REFERENCES Bee KJ et al CJ. TGFBRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor B2 signal transduction. Circ Cardiovasc Genet. 2012 Dec;5(6):621-9. PMID: 23099432.

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 rs138262219 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:

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 rs138262219 ...

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.94+16293C>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138262219 ...