VCV000213939.28 - ClinVar

NM_003242.6(TGFBR2):c.367A>T (p.Met123Leu)

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.

(12)

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); Uncertain risk allele(1); Likely benign(4)

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.367A>T (p.Met123Leu)

Variation ID: 213939 Accession: VCV000213939.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30650373 (GRCh38) [ NCBI UCSC ] 3: 30691865 (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 6, 2016	May 1, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.367A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Met123Leu	missense
NM_001024847.3:c.442A>T	NP_001020018.1:p.Met148Leu	missense
NM_001407126.1:c.442A>T	NP_001394055.1:p.Met148Leu	missense
NM_001407127.1:c.367A>T	NP_001394056.1:p.Met123Leu	missense
NM_001407128.1:c.394A>T	NP_001394057.1:p.Met132Leu	missense
NM_001407129.1:c.262A>T	NP_001394058.1:p.Met88Leu	missense
NM_001407130.1:c.367A>T	NP_001394059.1:p.Met123Leu	missense
NM_001407132.1:c.262A>T	NP_001394061.1:p.Met88Leu	missense
NM_001407133.1:c.262A>T	NP_001394062.1:p.Met88Leu	missense
NM_001407134.1:c.262A>T	NP_001394063.1:p.Met88Leu	missense
NM_001407135.1:c.262A>T	NP_001394064.1:p.Met88Leu	missense
NM_001407136.1:c.262A>T	NP_001394065.1:p.Met88Leu	missense
NM_001407139.1:c.442A>T	NP_001394068.1:p.Met148Leu	missense
NC_000003.12:g.30650373A>T
NC_000003.11:g.30691865A>T
NG_007490.1:g.48872A>T
LRG_779:g.48872A>T
LRG_779t1:c.442A>T	LRG_779p1:p.Met148Leu
LRG_779t2:c.367A>T	LRG_779p2:p.Met123Leu

... more HGVS ... less HGVS

Protein change

M123L, M148L, M132L, M88L

Other names

p.M123L:ATG>TTG

Canonical SPDI

NC_000003.12:30650372:A:T

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 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00005

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD) 0.00010

Links

ClinGen: CA048064 dbSNP: rs768385200 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	1174	1201

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 specified	Uncertain significance (1)	criteria provided, single submitter	Jan 6, 2017	RCV000198358.11
Familial thoracic aortic aneurysm and aortic dissection	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000253449.23
Marfan syndrome	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000380176.6
Loeys-Dietz syndrome	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000323333.6
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Mar 11, 2022	RCV000766907.6
Diabetic retinopathy	Uncertain risk allele (1)	criteria provided, single submitter	-	RCV004020382.1
Loeys-Dietz syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Feb 5, 2024	RCV003996930.2

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.
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Marfan Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000442836.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely 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: SCV000442835.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely 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: SCV000442837.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jan 06, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605376.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Uncertain significance (Nov 01, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000250960.13 First in ClinVar: Oct 11, 2015 Last updated: May 02, 2019	Comment: The M123L variant of uncertain significance in the TGFBR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant … (more) The M123L variant of uncertain significance in the TGFBR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The M123L variant has been identified in several other individuals referred for Marfan/TAAD genetic testing at GeneDx; however, the majority of individuals harbored a second cardiogenetic variant. This substitution occurs at a position that is conserved across species, and the majority of in silico tools predict this variant is probably damaging to the protein structure/function. Nevertheless, the M123L variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less)
Likely 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: SCV000658829.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Mar 08, 2023)	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: SCV000320500.6 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: The p.M123L variant (also known as c.367A>T), located in coding exon 3 of the TGFBR2 gene, results from an A to T substitution at nucleotide … (more) The p.M123L variant (also known as c.367A>T), located in coding exon 3 of the TGFBR2 gene, results from an A to T substitution at nucleotide position 367. The methionine at codon 123 is replaced by leucine, an amino acid with some highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Uncertain significance (Mar 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003819486.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Nov 29, 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: SCV001358499.3 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Comment: This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction tool indicates that this variant may have an uncertain … (more) This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 11/282168 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 (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: SCV004839160.1 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)	Comment: This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282168 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) Number of individuals with the variant: 14 Zygosity: Single Heterozygote
Uncertain risk allele (-)	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: SCV005016460.1 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 rs768385200 with diabetic retinopathy. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553491.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The TGFBR2 p.Met123Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs768385200), LOVD … (more) The TGFBR2 p.Met123Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs768385200), LOVD 3.0 and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, ARUP Laboratories and Invitae, and as likely benign by Illumina). The variant was identified in control databases in 9 of 267632 chromosomes at a frequency of 0.00003363 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Other in 2 of 6684 chromosomes (freq: 0.000299), East Asian in 3 of 19248 chromosomes (freq: 0.000156), Latino in 3 of 35078 chromosomes (freq: 0.000086) and African in 1 of 23596 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, European (Finnish), European (non-Finnish), or South Asian populations. The p.Met123 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Comment:

The M123L variant of uncertain significance in the TGFBR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The M123L variant has been identified in several other individuals referred for Marfan/TAAD genetic testing at GeneDx; however, the majority of individuals harbored a second cardiogenetic variant. This substitution occurs at a position that is conserved across species, and the majority of in silico tools predict this variant is probably damaging to the protein structure/function. Nevertheless, the M123L variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

Comment:

The p.M123L variant (also known as c.367A>T), located in coding exon 3 of the TGFBR2 gene, results from an A to T substitution at nucleotide position 367. The methionine at codon 123 is replaced by leucine, an amino acid with some highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Comment:

This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 11/282168 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 missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282168 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:

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 rs768385200 with diabetic retinopathy.

Comment:

The TGFBR2 p.Met123Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs768385200), LOVD 3.0 and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, ARUP Laboratories and Invitae, and as likely benign by Illumina). The variant was identified in control databases in 9 of 267632 chromosomes at a frequency of 0.00003363 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Other in 2 of 6684 chromosomes (freq: 0.000299), East Asian in 3 of 19248 chromosomes (freq: 0.000156), Latino in 3 of 35078 chromosomes (freq: 0.000086) and African in 1 of 23596 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, European (Finnish), European (non-Finnish), or South Asian populations. The p.Met123 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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
Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy.	Platania CBM	Biochemical pharmacology	2018	PMID: 30222965
The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels.	Dagher Z	The American journal of pathology	2017	PMID: 28162229

Text-mined citations for rs768385200 ...

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.367A>T (p.Met123Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs768385200 ...