ClinVar Genomic variation as it relates to human health
NM_004612.4(TGFBR1):c.1060C>A (p.Leu354Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004612.4(TGFBR1):c.1060C>A (p.Leu354Met)
Variation ID: 1806085 Accession: VCV001806085.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.33 9: 99144818 (GRCh38) [ NCBI UCSC ] 9: 101907100 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 24, 2022 Dec 24, 2022 Sep 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004612.4:c.1060C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004603.1:p.Leu354Met missense NM_001130916.3:c.829C>A NP_001124388.1:p.Leu277Met missense NM_001306210.2:c.1072C>A NP_001293139.1:p.Leu358Met missense NM_001407416.1:c.904C>A NP_001394345.1:p.Leu302Met missense NM_001407417.1:c.892C>A NP_001394346.1:p.Leu298Met missense NM_001407418.1:c.865C>A NP_001394347.1:p.Leu289Met missense NM_001407419.1:c.865C>A NP_001394348.1:p.Leu289Met missense NM_001407420.1:c.865C>A NP_001394349.1:p.Leu289Met missense NM_001407422.1:c.865C>A NP_001394351.1:p.Leu289Met missense NM_001407423.1:c.853C>A NP_001394352.1:p.Leu285Met missense NM_001407424.1:c.853C>A NP_001394353.1:p.Leu285Met missense NM_001407425.1:c.853C>A NP_001394354.1:p.Leu285Met missense NM_001407426.1:c.853C>A NP_001394355.1:p.Leu285Met missense NM_001407427.1:c.853C>A NP_001394356.1:p.Leu285Met missense NM_001407428.1:c.853C>A NP_001394357.1:p.Leu285Met missense NM_001407429.1:c.853C>A NP_001394358.1:p.Leu285Met missense NM_001407430.1:c.853C>A NP_001394359.1:p.Leu285Met missense NM_001407432.1:c.853C>A NP_001394361.1:p.Leu285Met missense NM_001407433.1:c.853C>A NP_001394362.1:p.Leu285Met missense NM_001407434.1:c.853C>A NP_001394363.1:p.Leu285Met missense NM_001407435.1:c.829C>A NP_001394364.1:p.Leu277Met missense NM_001407436.1:c.814C>A NP_001394365.1:p.Leu272Met missense NM_001407437.1:c.352C>A NP_001394366.1:p.Leu118Met missense NM_001407438.1:c.583C>A NP_001394367.1:p.Leu195Met missense NR_176360.1:n.1289C>A NR_176361.1:n.1153C>A NR_176362.1:n.1165C>A NR_176363.1:n.1153C>A NC_000009.12:g.99144818C>A NC_000009.11:g.101907100C>A NG_007461.1:g.44689C>A - Protein change
- L118M, L195M, L272M, L277M, L285M, L289M, L298M, L302M, L354M, L358M
- Other names
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- Canonical SPDI
- NC_000009.12:99144817:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TGFBR1 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2022 | RCV002470369.1 |
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
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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
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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
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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. |
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Likely pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767158.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic (pending) . Following criteria are met: 0102 - Loss of function is … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic (pending) . Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, missense variants have been postulated to exert a dominant negative effect. Both mechanisms are associated with Loeys-Dietz syndrome (MIM#609192) (PMID: 30701076). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is considerable variability in the phenotype, from mild features to severe systemic abnormalities (PMID: 32339686). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Leu354Pro) was identified in an individual with Loeys-Dietz syndrome (PMID: 18852674) and classified as likely pathogenic by a diagnostic laboratory in ClinVar. p.(Leu354Arg) (annotated as Leu277Arg in the paper) was identified in an individual with thoracic aortic aneurysm (PMID: 28550590). (SP) 0807 - This variant has no previous evidence of pathogenicity. (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)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Type A Aortic Dissection Caused by Loeys-Dietz Syndrome with Novel Variation. | Skeik N | Annals of vascular surgery | 2020 | PMID: 32339686 |
Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1. | Hara H | Human genome variation | 2019 | PMID: 30701076 |
Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity. | Landis BJ | Journal of cardiovascular translational research | 2017 | PMID: 28550590 |
Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). | Maleszewski JJ | The American journal of surgical pathology | 2009 | PMID: 18852674 |
Text-mined citations for this variant ...
HelpRecord last updated Mar 26, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.