VCV000213936.8 - ClinVar

NM_003242.6(TGFBR2):c.1564G>A (p.Asp522Asn)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 3 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003242.6(TGFBR2):c.1564G>A (p.Asp522Asn)

Variation ID: 213936 Accession: VCV000213936.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30691459 (GRCh38) [ NCBI UCSC ] 3: 30732951 (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	Oct 11, 2015	Feb 25, 2025	Jul 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.1564G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Asp522Asn	missense
NM_001024847.3:c.1639G>A	NP_001020018.1:p.Asp547Asn	missense
NM_001407126.1:c.1747G>A	NP_001394055.1:p.Asp583Asn	missense
NM_001407127.1:c.1672G>A	NP_001394056.1:p.Asp558Asn	missense
NM_001407128.1:c.1591G>A	NP_001394057.1:p.Asp531Asn	missense
NM_001407129.1:c.1567G>A	NP_001394058.1:p.Asp523Asn	missense
NM_001407130.1:c.1561G>A	NP_001394059.1:p.Asp521Asn	missense
NM_001407132.1:c.1459G>A	NP_001394061.1:p.Asp487Asn	missense
NM_001407133.1:c.1459G>A	NP_001394062.1:p.Asp487Asn	missense
NM_001407134.1:c.1459G>A	NP_001394063.1:p.Asp487Asn	missense
NM_001407135.1:c.1459G>A	NP_001394064.1:p.Asp487Asn	missense
NM_001407136.1:c.1459G>A	NP_001394065.1:p.Asp487Asn	missense
NM_001407137.1:c.1279G>A	NP_001394066.1:p.Asp427Asn	missense
NM_001407138.1:c.1204G>A	NP_001394067.1:p.Asp402Asn	missense
NM_001407139.1:c.694G>A	NP_001394068.1:p.Asp232Asn	missense
NC_000003.12:g.30691459G>A
NC_000003.11:g.30732951G>A
NG_007490.1:g.89958G>A
LRG_779:g.89958G>A
LRG_779t1:c.1639G>A	LRG_779p1:p.Asp547Asn
LRG_779t2:c.1564G>A	LRG_779p2:p.Asp522Asn

... more HGVS ... less HGVS

Protein change

D522N, D547N, D521N, D523N, D558N, D402N, D427N, D531N, D232N, D487N, D583N

Other names

p.D522N:GAC>AAC

Canonical SPDI

NC_000003.12:30691458:G:A

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

ClinGen: CA322561 dbSNP: rs863223854 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	1319	1346

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	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 12, 2024	RCV000198083.4
Familial thoracic aortic aneurysm and aortic dissection	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 3, 2022	RCV000704530.8

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.	Expand all rows Collapse all rows 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.
Pathogenic (Jul 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial thoracic aortic aneurysm and aortic dissection	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000833482.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 28492532‚ 17599521‚ 30675029‚ 34422331 Comment: show For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 522 of the TGFBR2 protein (p.Asp522Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 17599521, 30675029, 34422331; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as NM_001024847.2:c.1639G>A (p.Asp547Asn). ClinVar contains an entry for this variant (Variation ID: 213936). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function. This variant disrupts the p.Asp522 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 20, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Thoracic aortic aneurysm and aortic dissection (Autosomal dominant inheritance)	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf Accession: SCV000897685.1 First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019	Publications: PubMed (1) PubMed: 30675029 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Uncertain significance (Dec 06, 2017) N Not contributing to aggregate classification	Flagged submission flagged submission (GeneDx Variant Classification (06012015)) Reason: Older claim that does not account for recent evidence Source: ClinGen	Not Provided	GeneDx Accession: SCV000250951.11 First in ClinVar: Oct 11, 2015 Last updated: Apr 17, 2019	Comment: show The D522N variant of uncertain significance in the TGFBR2 gene has been reported in an individual with a clinical diagnosis of Loeys Dietz syndrome (LDS) and classic features (Lee et al., 2007); however, segregation information was not provided. This variant is not observed in large population cohorts (Lek et al., 2016). The D522N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the D522N variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Finally, while missense variants in nearby residues (G520R, G520F, G520Y, W521R, D524N, D524Y) have been reported in HGMD in association with TGFBR2-related disorders (Stenson et al., 2014); the pathogenicity of these variants has not been definitively determined. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 522 of the TGFBR2 protein (p.Asp522Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 17599521, 30675029, 34422331; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as NM_001024847.2:c.1639G>A (p.Asp547Asn). ClinVar contains an entry for this variant (Variation ID: 213936). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function. This variant disrupts the p.Asp522 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue.

Comment:

The D522N variant of uncertain significance in the TGFBR2 gene has been reported in an individual with a clinical diagnosis of Loeys Dietz syndrome (LDS) and classic features (Lee et al., 2007); however, segregation information was not provided. This variant is not observed in large population cohorts (Lek et al., 2016). The D522N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the D522N variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Finally, while missense variants in nearby residues (G520R, G520F, G520Y, W521R, D524N, D524Y) have been reported in HGMD in association with TGFBR2-related disorders (Stenson et al., 2014); the pathogenicity of these variants has not been definitively determined.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic variants in Chinese patients with sporadic Stanford type A aortic dissection.	Chen ZR	Journal of thoracic disease	2021	PMID: 34422331
Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.	Renner S	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30675029
Rapid aneurysmal degeneration of a Stanford type B aortic dissection in a patient with Loeys-Dietz syndrome.	Lee RS	The Journal of thoracic and cardiovascular surgery	2007	PMID: 17599521

Text-mined citations for rs863223854 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_003242.6(TGFBR2):c.1564G>A (p.Asp522Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs863223854 ...