VCV000036865.37 - ClinVar

NM_003242.6(TGFBR2):c.1266A>G (p.Ala422=)

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.

(15)

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.

Benign

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.1266A>G (p.Ala422=)

Variation ID: 36865 Accession: VCV000036865.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30674116 (GRCh38) [ NCBI UCSC ] 3: 30715608 (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	Apr 4, 2013	Sep 29, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.1266A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Ala422=	synonymous
NM_001024847.3:c.1341A>G	NP_001020018.1:p.Ala447=	synonymous
NM_001407126.1:c.1449A>G	NP_001394055.1:p.Ala483=	synonymous
NM_001407127.1:c.1374A>G	NP_001394056.1:p.Ala458=	synonymous
NM_001407128.1:c.1293A>G	NP_001394057.1:p.Ala431=	synonymous
NM_001407129.1:c.1269A>G	NP_001394058.1:p.Ala423=	synonymous
NM_001407130.1:c.1266A>G	NP_001394059.1:p.Ala422=	synonymous
NM_001407132.1:c.1161A>G	NP_001394061.1:p.Ala387=	synonymous
NM_001407133.1:c.1161A>G	NP_001394062.1:p.Ala387=	synonymous
NM_001407134.1:c.1161A>G	NP_001394063.1:p.Ala387=	synonymous
NM_001407135.1:c.1161A>G	NP_001394064.1:p.Ala387=	synonymous
NM_001407136.1:c.1161A>G	NP_001394065.1:p.Ala387=	synonymous
NM_001407137.1:c.981A>G	NP_001394066.1:p.Ala327=	synonymous
NM_001407138.1:c.906A>G	NP_001394067.1:p.Ala302=	synonymous
NM_001407139.1:c.530-14271A>G		intron variant
NC_000003.12:g.30674116A>G
NC_000003.11:g.30715608A>G
NG_007490.1:g.72615A>G
LRG_779:g.72615A>G
LRG_779t1:c.1341A>G	LRG_779p1:p.Ala447=
LRG_779t2:c.1266A>G	LRG_779p2:p.Ala422=

... more HGVS ... less HGVS

Protein change

Other names

p.A422A:GCA>GCG

Canonical SPDI

NC_000003.12:30674115:A: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.

0.03115 (G)

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

The Genome Aggregation Database (gnomAD), exomes 0.00702

Exome Aggregation Consortium (ExAC) 0.00878

The Genome Aggregation Database (gnomAD) 0.02974

Trans-Omics for Precision Medicine (TOPMed) 0.03094

1000 Genomes Project 0.03115

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03160

1000 Genomes Project 30x 0.03310

Links

ClinGen: CA020636 dbSNP: rs2228047 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	1171	1198

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.
Loeys-Dietz syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Jun 14, 2016	RCV000030547.15
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Oct 26, 2012	RCV000037731.22
Familial thoracic aortic aneurysm and aortic dissection	Benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000253560.28
Loeys-Dietz syndrome 2	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000370024.15
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jul 7, 2015	RCV000617140.9
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Aug 14, 2021	RCV001811224.14
Ehlers-Danlos syndrome	Benign (1)	criteria provided, single submitter	Aug 13, 2021	RCV002277110.10

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000309518.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 14, 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: SCV000884688.3 First in ClinVar: Feb 18, 2019 Last updated: Jan 08, 2022
Benign (Oct 26, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000168943.10 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 16, 2018)	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: SCV000902791.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (Aug 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566152.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Benign (Dec 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239742.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Thoracic Aortic Aneurysms and Aortic Dissections Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442891.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Loeys-Dietz Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442889.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jan 21, 2009)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061393.6 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Publications: PubMed (1) PubMed: 18781618 Number of individuals with the variant: 10
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Loeys-Dietz syndrome 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442890.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jul 07, 2015)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000317709.5 First in ClinVar: Oct 02, 2016 Last updated: Apr 13, 2018	Comment: This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more) This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Number of individuals with the variant: 1
benign (Aug 18, 2011)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Loeys-Dietz Syndrome (autosomal unknown) Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000053218.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022	Publications: PubMed (1) PubMed: 18781618 Comment: Converted during submission to Benign. Observation 1: Tissue: Blood Observation 2: Tissue: Blood Observation 3: Tissue: Blood
Benign (Jan 31, 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: SCV000559159.8 First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005242320.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Feb 05, 2024)	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: SCV004841419.1 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)	Number of individuals with the variant: 1646
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders.	Stheneur C	Human mutation	2008	PMID: 18781618

Text-mined citations for rs2228047 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_003242.6(TGFBR2):c.1266A>G (p.Ala422=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2228047 ...