VCV002033852.3 - ClinVar

NM_004612.4(TGFBR1):c.839C>G (p.Ser280Ter)

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.

(2)

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
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004612.4(TGFBR1):c.839C>G (p.Ser280Ter)

Variation ID: 2033852 Accession: VCV002033852.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.33 9: 99142569 (GRCh38) [ NCBI UCSC ] 9: 101904851 (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	Feb 8, 2023	Feb 20, 2024	Jan 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004612.4:c.839C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004603.1:p.Ser280Ter	nonsense
NM_001130916.3:c.608C>G	NP_001124388.1:p.Ser203Ter	nonsense
NM_001306210.2:c.851C>G	NP_001293139.1:p.Ser284Ter	nonsense
NM_001407418.1:c.644C>G	NP_001394347.1:p.Ser215Ter	nonsense
NM_001407419.1:c.644C>G	NP_001394348.1:p.Ser215Ter	nonsense
NM_001407420.1:c.644C>G	NP_001394349.1:p.Ser215Ter	nonsense
NM_001407422.1:c.644C>G	NP_001394351.1:p.Ser215Ter	nonsense
NM_001407423.1:c.632C>G	NP_001394352.1:p.Ser211Ter	nonsense
NM_001407424.1:c.632C>G	NP_001394353.1:p.Ser211Ter	nonsense
NM_001407425.1:c.632C>G	NP_001394354.1:p.Ser211Ter	nonsense
NM_001407426.1:c.632C>G	NP_001394355.1:p.Ser211Ter	nonsense
NM_001407427.1:c.632C>G	NP_001394356.1:p.Ser211Ter	nonsense
NM_001407428.1:c.632C>G	NP_001394357.1:p.Ser211Ter	nonsense
NM_001407429.1:c.632C>G	NP_001394358.1:p.Ser211Ter	nonsense
NM_001407430.1:c.632C>G	NP_001394359.1:p.Ser211Ter	nonsense
NM_001407432.1:c.632C>G	NP_001394361.1:p.Ser211Ter	nonsense
NM_001407433.1:c.632C>G	NP_001394362.1:p.Ser211Ter	nonsense
NM_001407434.1:c.632C>G	NP_001394363.1:p.Ser211Ter	nonsense
NM_001407435.1:c.608C>G	NP_001394364.1:p.Ser203Ter	nonsense
NM_001407436.1:c.593C>G	NP_001394365.1:p.Ser198Ter	nonsense
NM_001407437.1:c.131C>G	NP_001394366.1:p.Ser44Ter	nonsense
NM_001407438.1:c.362C>G	NP_001394367.1:p.Ser121Ter	nonsense
NM_004612.2:c.839C>G
NR_176360.1:n.1068C>G
NR_176361.1:n.932C>G
NR_176362.1:n.944C>G
NR_176363.1:n.932C>G
NC_000009.12:g.99142569C>G
NC_000009.11:g.101904851C>G
NG_007461.1:g.42440C>G

... more HGVS ... less HGVS

Protein change

S203*, S211*, S280*, S284*, S198*, S121*, S215*, S44*

Other names

Canonical SPDI

NC_000009.12:99142568:C:G

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.

Links

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.
TGFBR1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-

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	Pathogenic (1)	criteria provided, single submitter	Oct 3, 2022	RCV002872687.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2023	RCV003314745.1

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 (Jan 13, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004014143.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge (less)
Pathogenic (Oct 03, 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: SCV003238005.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 21358634 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser280*) in the TGFBR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGFBR1 are known to be pathogenic (PMID: 21358634). (less)

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser280*) in the TGFBR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGFBR1 are known to be pathogenic (PMID: 21358634).

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
Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1.	Goudie DR	Nature genetics	2011	PMID: 21358634

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004612.4(TGFBR1):c.839C>G (p.Ser280Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...