VCV000560163.12 - ClinVar

NM_005359.6(SMAD4):c.290G>T (p.Arg97Leu)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

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_005359.6(SMAD4):c.290G>T (p.Arg97Leu)

Variation ID: 560163 Accession: VCV000560163.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q21.2 18: 51048726 (GRCh38) [ NCBI UCSC ] 18: 48575096 (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	Aug 31, 2018	Aug 3, 2025	Jan 20, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_005359.6:c.290G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005350.1:p.Arg97Leu	missense
NC_000018.10:g.51048726G>T
NC_000018.9:g.48575096G>T
NG_013013.2:g.85687G>T
LRG_318:g.85687G>T
LRG_318t1:c.290G>T	LRG_318p1:p.Arg97Leu

... more HGVS ... less HGVS

Protein change

R97L

Other names

Canonical SPDI

NC_000018.10:51048725:G:T

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: CA402458253 dbSNP: rs1555685159 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.
SMAD4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2538	2580

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.
Heritable Thoracic Aortic Disease	Likely pathogenic (1)	criteria provided, single submitter	Apr 1, 2018	RCV000678041.3
Juvenile polyposis syndrome	Uncertain significance (1)	criteria provided, single submitter	Jan 20, 2020	RCV001304441.9
Heritable thoracic aortic disease without juvenile polyposis and hereditary hemorrhagic telangiectasia	Likely pathogenic (1)	no assertion criteria provided	-	RCV001261772.1

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.
Uncertain significance (Jan 20, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Juvenile polyposis syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001493721.6 First in ClinVar: Mar 07, 2021 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 30809044 Comment: show This variant has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 30809044). ClinVar contains an entry for this variant (Variation ID: 560163). This sequence change replaces arginine with leucine at codon 97 of the SMAD4 protein (p.Arg97Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to affect SMAD4 protein function (PMID: 30809044). 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

Likely pathogenic (Apr 01, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Heritable Thoracic Aortic Disease	Department of Internal Medicine, The University of Texas McGovern Medical School, The University of Texas Health Science Center at Houston Accession: SCV000804195.3 First in ClinVar: Aug 31, 2018 Last updated: Aug 03, 2025	Comment: show This variant was identified in a family with thoracic aortic disease and no evidence of juvenile polyposis and/or hereditary hemorrhagic telangiectasia (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Number of individuals with the variant: 3 Age: 33-75 years Sex: mixed Comment on evidence: "effect on RNA stability" was previously submitted as the functional consequence for NM_005359.5:c.290G>T, but without providing the result of a functional assay.

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Heritable thoracic aortic disease without juvenile polyposis and hereditary hemorrhagic telangiectasia	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001439088.1 First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020	Publications: PubMed (1) PubMed: 30809044 Observation: 1 Collection method: research Allele origin: inherited Affected status: yes Observation 1 Collection method: research Allele origin: inherited Affected status: yes

Comment:

This variant has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 30809044). ClinVar contains an entry for this variant (Variation ID: 560163). This sequence change replaces arginine with leucine at codon 97 of the SMAD4 protein (p.Arg97Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to affect SMAD4 protein function (PMID: 30809044). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections.	Duan XY	European journal of human genetics : EJHG	2019	PMID: 30809044

Text-mined citations for rs1555685159 ...

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 Aug 03, 2025

ClinVar Genomic variation as it relates to human health

NM_005359.6(SMAD4):c.290G>T (p.Arg97Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs1555685159 ...