VCV000477546.31 - ClinVar

NM_003242.6(TGFBR2):c.383del (p.Lys128fs)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (4); Benign (2); Likely benign (1)

8 out of 11 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

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_003242.6(TGFBR2):c.383del (p.Lys128fs)

Variation ID: 477546 Accession: VCV000477546.31

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p24.1 3: 30650380 (GRCh38) [ NCBI UCSC ] 3: 30691872 (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 26, 2017	Feb 15, 2026	Jan 26, 2026
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.383del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.Lys128fs	frameshift
NM_003242.6:c.383delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001024847.3:c.458delA	NP_001020018.1:p.Lys153Serfs	frameshift
NM_001407126.1:c.458delA	NP_001394055.1:p.Lys153Serfs	frameshift
NM_001407127.1:c.383delA	NP_001394056.1:p.Lys128Serfs	frameshift
NM_001407128.1:c.410delA	NP_001394057.1:p.Lys137Serfs	frameshift
NM_001407129.1:c.278delA	NP_001394058.1:p.Lys93Serfs	frameshift
NM_001407130.1:c.383delA	NP_001394059.1:p.Lys128Serfs	frameshift
NM_001407132.1:c.278delA	NP_001394061.1:p.Lys93Serfs	frameshift
NM_001407133.1:c.278delA	NP_001394062.1:p.Lys93Serfs	frameshift
NM_001407134.1:c.278delA	NP_001394063.1:p.Lys93Serfs	frameshift
NM_001407135.1:c.278delA	NP_001394064.1:p.Lys93Serfs	frameshift
NM_001407136.1:c.278delA	NP_001394065.1:p.Lys93Serfs	frameshift
NM_001407139.1:c.458delA	NP_001394068.1:p.Lys153Serfs	frameshift
NM_003242.5:c.383del
NC_000003.12:g.30650389del
NC_000003.11:g.30691881del
NG_007490.1:g.48888del
LRG_779:g.48888del
LRG_779t1:c.458del	LRG_779p1:p.Lys153fs
LRG_779t2:c.383del	LRG_779p2:p.Lys128fs

... more HGVS ... less HGVS

Protein change

K153fs, K128fs

Other names

Canonical SPDI

NC_000003.12:30650379:AAAAAAAAAA:AAAAAAAAA

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: CA048107 dbSNP: rs79375991 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	1415	1445

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	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Dec 19, 2025	RCV000559144.21
Loeys-Dietz syndrome	Likely pathogenic (1)	criteria provided, single submitter	Mar 10, 2018	RCV000680445.10
not specified	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Jan 26, 2026	RCV001001460.19
not provided	Uncertain significance (2)	criteria provided, single submitter	May 29, 2024	RCV001702809.10
Loeys-Dietz syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Sep 10, 2025	RCV005860105.1

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.	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.
Benign (Feb 09, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	not specified	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158709.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	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 benign (Jun 25, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial thoracic aortic aneurysm and aortic dissection	Color Diagnostics, LLC DBA Color Health Accession: SCV001735851.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Benign (May 06, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Familial thoracic aortic aneurysm and aortic dissection	Ambry Genetics Accession: SCV000739846.5 First in ClinVar: Apr 16, 2018 Last updated: May 01, 2024	Comment: show This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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) 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 (Mar 10, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Loeys-Dietz syndrome	GeneID Lab - Advanced Molecular Diagnostics Accession: SCV000807818.2 First in ClinVar: Sep 24, 2018 Last updated: Apr 13, 2025	Comment: show This variant results in an amino acid alteration replacing a lysine (K) with a serine (S) at position 128 creating a premature stop signal in the new reading frame noted as p K128Sfs*35. The substitution is predicted to result in a non-functional TGFBR2 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the ClinVar Database (NCBI National Library of Medicine, NIH, Bethesda MD), but it has been described in 3478 alleles out of 85936, in the ExAC database, all of them belonging to heterozygous carries of Latino origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Age: 20-29 years Sex: female Ethnicity/Population group: Latin American Geographic origin: United States

Uncertain significance (Dec 19, 2025) 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: SCV000658831.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 26948038‚ 37937776 Comment: show This sequence change creates a premature translational stop signal (p.Lys128Serfs*35) in the TGFBR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TGFBR2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 26948038, 37937776). ClinVar contains an entry for this variant (Variation ID: 477546). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Uncertain significance (May 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005419540.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: show Frameshift 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; This variant is associated with the following publications: (PMID: 26948038, 28847661, 29951173, 23578328, 33105726, 31779681, 23585368, 34102952) (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

Uncertain significance (Sep 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Loeys-Dietz syndrome 2	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV006553010.1 First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV007344250.1 First in ClinVar: Feb 07, 2026 Last updated: Feb 07, 2026	Publications: PubMed (2) PubMed: 26948038‚ 7761852 Comment: show Variant summary: TGFBR2 c.383delA (p.Lys128SerfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.383delA has been observed in an individual affected with Loeys-Dietz syndrome 2 without clear evidence for causality (Wei_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Loeys-Dietz syndrome 2. One publication reports experimental evidence evaluating an impact on protein function (Markowitz_1995), however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 7761852, 26948038). ClinVar contains an entry for this variant (Variation ID: 477546). Based on the evidence outlined above, the variant was classified as uncertain significance. (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

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740432.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001928220.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV001965452.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.

Comment:

This variant results in an amino acid alteration replacing a lysine (K) with a serine (S) at position 128 creating a premature stop signal in the new reading frame noted as p K128Sfs*35. The substitution is predicted to result in a non-functional TGFBR2 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the ClinVar Database (NCBI National Library of Medicine, NIH, Bethesda MD), but it has been described in 3478 alleles out of 85936, in the ExAC database, all of them belonging to heterozygous carries of Latino origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant.

Comment:

This sequence change creates a premature translational stop signal (p.Lys128Serfs*35) in the TGFBR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TGFBR2 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 26948038, 37937776). ClinVar contains an entry for this variant (Variation ID: 477546). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Frameshift 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; This variant is associated with the following publications: (PMID: 26948038, 28847661, 29951173, 23578328, 33105726, 31779681, 23585368, 34102952)

Comment:

Variant summary: TGFBR2 c.383delA (p.Lys128SerfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.383delA has been observed in an individual affected with Loeys-Dietz syndrome 2 without clear evidence for causality (Wei_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Loeys-Dietz syndrome 2. One publication reports experimental evidence evaluating an impact on protein function (Markowitz_1995), however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 7761852, 26948038). ClinVar contains an entry for this variant (Variation ID: 477546). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Actionable Genotypes and Their Association with Life Span in Iceland.	Jensson BO	The New England journal of medicine	2023	PMID: 37937776
Successful Single-Stage Operation for Loeys-Dietz Syndrome With Critical Coarctation of the Descending Aorta in a Young Adult.	Wei S	The Canadian journal of cardiology	2016	PMID: 26948038
Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.	Markowitz S	Science (New York, N.Y.)	1995	PMID: 7761852

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Likely oncogenic criteria provided, single submitter	Mar 4, 2025	RCV004669042.2

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Likely oncogenic (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)	Neoplasm	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005094492.2 First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs79375991 ...

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 Apr 13, 2026