VCV000408434.18 - ClinVar

NM_003242.6(TGFBR2):c.95-3C>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.

(7)

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(6); 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.95-3C>A

Variation ID: 408434 Accession: VCV000408434.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30644744 (GRCh38) [ NCBI UCSC ] 3: 30686236 (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	Jul 23, 2024	Jan 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.95-3C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001024847.3:c.170-3C>A		intron variant
NM_001407126.1:c.170-3C>A		intron variant
NM_001407127.1:c.95-3C>A		intron variant
NM_001407128.1:c.122-3C>A		intron variant
NM_001407129.1:c.-11-3C>A		intron variant
NM_001407130.1:c.95-3C>A		intron variant
NM_001407132.1:c.-11-3C>A		intron variant
NM_001407133.1:c.-11-3C>A		intron variant
NM_001407134.1:c.-11-3C>A		intron variant
NM_001407135.1:c.-11-3C>A		intron variant
NM_001407136.1:c.-11-3C>A		intron variant
NM_001407137.1:c.169+21471C>A		intron variant
NM_001407138.1:c.95-26894C>A		intron variant
NM_001407139.1:c.170-3C>A		intron variant
NC_000003.12:g.30644744C>A
NC_000003.11:g.30686236C>A
NG_007490.1:g.43243C>A
LRG_779:g.43243C>A
LRG_779t2:c.95-3C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:30644743: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 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA050622 dbSNP: rs375330013 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	Jan 6, 2024	RCV000462907.13
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 4, 2020	RCV000497514.4
Loeys-Dietz syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Jun 24, 2022	RCV002272243.3
Colorectal cancer, hereditary nonpolyposis, type 6 Loeys-Dietz syndrome 2 Malignant tumor of esophagus	Uncertain significance (1)	criteria provided, single submitter	Oct 14, 2021	RCV002489047.1
Diabetic retinopathy	Likely benign (1)	criteria provided, single submitter	-	RCV004022691.1

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 (Aug 04, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589371.2 First in ClinVar: Aug 20, 2017 Last updated: Dec 19, 2017	Comment: Identified in one individual referred for aortopathy genetic testing in the published literature (Wooderchak-Donahue et al., 2015); In-silico analysis, which includes splice predictors and evolutionary … (more) Identified in one individual referred for aortopathy genetic testing in the published literature (Wooderchak-Donahue et al., 2015); In-silico analysis, which includes splice predictors and evolutionary conservation, 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; This variant is associated with the following publications: (PMID: 25944730) (less)
Uncertain significance (Oct 14, 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: SCV002780763.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (May 12, 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: SCV001348648.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 25944730 Comment: This variant is located close to intron 2 canonical splice acceptor site of the TGFBR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding … (more) This variant is located close to intron 2 canonical splice acceptor site of the TGFBR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual referred for aortopathy testing (PMID: 25944730). This variant has been identified in 6/282146 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 (Jan 06, 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: SCV000548108.5 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 25944730‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 1 of the TGFBR2 gene. It does not directly change the encoded amino acid sequence of the TGFBR2 protein. … (more) This sequence change falls in intron 1 of the TGFBR2 gene. It does not directly change the encoded amino acid sequence of the TGFBR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375330013, gnomAD 0.005%). This variant has been observed in individual(s) with aortopathy (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 408434). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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)
Likely benign (-)	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: SCV005016416.1 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 rs375330013 with diabetic retinopathy. (less)
Uncertain significance (Dec 23, 2020)	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: SCV002694605.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25944730 Comment: The c.95-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the TGFBR2 gene. This alteration has … (more) The c.95-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the TGFBR2 gene. This alteration has been reported in a cohort of individuals referred for aortopathy panel genetic testing, but clinical details were limited (Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Loeys-Dietz syndrome 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557280.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 15731757‚ 25944730‚ 28679693‚ 32528524 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are mechanisms of disease in this gene and are associated with Loeys-Dietz syndrome 2 (MIM#610168). Both LoF and GoF have been demonstrated as potential disease mechanisms in patients with Loeys-Dietz syndrome 2 (GeneReview, PMID: 15731757, 32528524, 28679693). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0710 - Other variants affecting the same nucleotide comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.95-3C>G and c.95-3C>T have both been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been regarded as a VUS both in ClinVar and in an individual with a suspected aortopathy (PMID: 25944730). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Identified in one individual referred for aortopathy genetic testing in the published literature (Wooderchak-Donahue et al., 2015); In-silico analysis, which includes splice predictors and evolutionary conservation, 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; This variant is associated with the following publications: (PMID: 25944730)

Comment:

This variant is located close to intron 2 canonical splice acceptor site of the TGFBR2 gene. Splice prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual referred for aortopathy testing (PMID: 25944730). This variant has been identified in 6/282146 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:

This sequence change falls in intron 1 of the TGFBR2 gene. It does not directly change the encoded amino acid sequence of the TGFBR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs375330013, gnomAD 0.005%). This variant has been observed in individual(s) with aortopathy (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 408434). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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:

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 rs375330013 with diabetic retinopathy.

Comment:

The c.95-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the TGFBR2 gene. This alteration has been reported in a cohort of individuals referred for aortopathy panel genetic testing, but clinical details were limited (Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are mechanisms of disease in this gene and are associated with Loeys-Dietz syndrome 2 (MIM#610168). Both LoF and GoF have been demonstrated as potential disease mechanisms in patients with Loeys-Dietz syndrome 2 (GeneReview, PMID: 15731757, 32528524, 28679693). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0710 - Other variants affecting the same nucleotide comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.95-3C>G and c.95-3C>T have both been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been regarded as a VUS both in ClinVar and in an individual with a suspected aortopathy (PMID: 25944730). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Identification of a Pathogenic TGFBR2 Variant in a Patient With Loeys-Dietz Syndrome.	Luo X	Frontiers in genetics	2020	PMID: 32528524
Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy.	Platania CBM	Biochemical pharmacology	2018	PMID: 30222965
Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys-Dietz syndrome (LDS) impairs canonical TGF-β signaling.	Cousin MA	Cold Spring Harbor molecular case studies	2017	PMID: 28679693
The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels.	Dagher Z	The American journal of pathology	2017	PMID: 28162229
Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.	Wooderchak-Donahue W	American journal of medical genetics. Part A	2015	PMID: 25944730
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.	Loeys BL	Nature genetics	2005	PMID: 15731757
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs375330013 ...

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.95-3C>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375330013 ...