VCV000139217.52 - ClinVar

NM_005902.4(SMAD3):c.309A>G (p.Leu103=)

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.

(21)

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_005902.4(SMAD3):c.309A>G (p.Leu103=)

Variation ID: 139217 Accession: VCV000139217.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.33 15: 67164997 (GRCh38) [ NCBI UCSC ] 15: 67457335 (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 2, 2016	Sep 29, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005902.4:c.309A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005893.1:p.Leu103=	synonymous
NM_001145102.2:c.-7A>G		5 prime UTR
NM_001145103.2:c.177A>G	NP_001138575.1:p.Leu59=	synonymous
NC_000015.10:g.67164997A>G
NC_000015.9:g.67457335A>G
NG_011990.1:g.104141A>G

... more HGVS ... less HGVS

Protein change

Other names

p.L103L:CTA>CTG

Canonical SPDI

NC_000015.10:67164996: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.

0.16594 (A)

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

1000 Genomes Project 0.83407

1000 Genomes Project 30x 0.83745

Exome Aggregation Consortium (ExAC) 0.86352

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.88000

The Genome Aggregation Database (gnomAD), exomes 0.86684

The Genome Aggregation Database (gnomAD) 0.87365

Trans-Omics for Precision Medicine (TOPMed) 0.87821

Links

ClinGen: CA019603 dbSNP: rs1065080 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.
SMAD3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1041	1105

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	Benign (9)	criteria provided, multiple submitters, no conflicts	Aug 9, 2019	RCV000128169.31
Familial thoracic aortic aneurysm and aortic dissection	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000247318.25
Aneurysm-osteoarthritis syndrome	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000989348.29
Thoracic aortic aneurysm	Benign (1)	no assertion criteria provided	Sep 23, 2022	RCV003148654.9
not provided	Benign (1)	criteria provided, single submitter	-	RCV004714505.1

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.	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 (Nov 02, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171761.12 First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 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: SCV000910495.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (May 09, 2019)	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: SCV002043353.1 First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021
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: SCV005293037.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
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: SCV000311291.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
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: SCV000393479.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Jul 17, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332954.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 14, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMAD3 Number of individuals with the variant: 2 Sex: mixed
Benign (Apr 04, 2013)	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: SCV000269835.3 First in ClinVar: May 29, 2016 Last updated: Feb 17, 2019	Comment: Leu103Leu in exon 2 of SMAD3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue … (more) Leu103Leu in exon 2 of SMAD3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 12.7% (560/4402) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1065080). (less) Number of individuals with the variant: 35
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Aneurysm-osteoarthritis syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139639.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Aneurysm-osteoarthritis syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000393480.3 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 (Aug 09, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362471.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020
Benign (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aneurysm-osteoarthritis syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002057751.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Benign (Feb 01, 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: SCV001729738.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Aneurysm-osteoarthritis syndrome Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605214.10 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aneurysm-osteoarthritis syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004815332.1 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: 104822
Benign (Nov 19, 2014)	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: SCV000317696.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	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 … (more) 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)
Benign (Nov 30, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740518.1 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808646.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967036.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744230.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (Sep 23, 2022)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Thoracic aortic aneurysm Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003836801.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
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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:

Leu103Leu in exon 2 of SMAD3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 12.7% (560/4402) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1065080).

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: 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.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMAD3	-	-	-	-

Text-mined citations for rs1065080 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_005902.4(SMAD3):c.309A>G (p.Leu103=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1065080 ...