VCV000213762.19 - ClinVar

NM_005902.4(SMAD3):c.733G>A (p.Gly245Arg)

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.

(4)

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.

Pathogenic/Likely pathogenic

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.733G>A (p.Gly245Arg)

Variation ID: 213762 Accession: VCV000213762.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q22.33 15: 67181315 (GRCh38) [ NCBI UCSC ] 15: 67473653 (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	Oct 13, 2024	Oct 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005902.4:c.733G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005893.1:p.Gly245Arg	missense
NM_001145102.2:c.418G>A	NP_001138574.1:p.Gly140Arg	missense
NM_001145103.2:c.601G>A	NP_001138575.1:p.Gly201Arg	missense
NM_001145104.2:c.148G>A	NP_001138576.1:p.Gly50Arg	missense
NC_000015.10:g.67181315G>A
NC_000015.9:g.67473653G>A
NG_011990.1:g.120459G>A

... more HGVS ... less HGVS

Protein change

G245R, G140R, G50R, G201R

Other names

p.G245R:GGG>AGG

Canonical SPDI

NC_000015.10:67181314:G:A

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.

Links

ClinGen: CA323714 dbSNP: rs863223737 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 provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 4, 2024	RCV000199185.15
Familial thoracic aortic aneurysm and aortic dissection	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 18, 2023	RCV000701533.18

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 pathogenic (Apr 17, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000927632.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Aorta Panel
Pathogenic (Nov 18, 2023)	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: SCV000830336.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 24804794‚ 29444731 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 245 of the SMAD3 protein (p.Gly245Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 245 of the SMAD3 protein (p.Gly245Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 24804794, 29444731; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213762). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function with a positive predictive value of 95%. This variant disrupts the p.Gly245 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Dec 13, 2022)	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: SCV000318611.8 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 24804794‚ 30661052 Comment: The p.G245R variant (also known as c.733G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide … (more) The p.G245R variant (also known as c.733G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide position 733. The glycine at codon 245 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with SMAD3-related phenotypes and has been reported to segregate with disease in a small number of affected relatives (Hostetler EM et al. J. Med. Genet., 2019 Apr;56:252-260; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). Internal structural analysis indicates that this variant causes a significant decrease in SMAD3 structural stability (Qin BY et al. Genes Dev. 2002 Aug;16(15):1950-63; Ambry internal data). A different alteration located at the same position, resulting in the same protein change, c.733G>C (p.G245R), has been reported in an individual with aortic root dilation (Arroyave J et al. Cardiol Young, 2018;28:765-767). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Likely pathogenic (Oct 04, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000250754.17 First in ClinVar: Oct 11, 2015 Last updated: Oct 13, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26221609, 28185953, 35830949, 30661052, 29444731, 32917565, 24804794) (less)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 245 of the SMAD3 protein (p.Gly245Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 24804794, 29444731; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213762). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function with a positive predictive value of 95%. This variant disrupts the p.Gly245 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.G245R variant (also known as c.733G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide position 733. The glycine at codon 245 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with SMAD3-related phenotypes and has been reported to segregate with disease in a small number of affected relatives (Hostetler EM et al. J. Med. Genet., 2019 Apr;56:252-260; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). Internal structural analysis indicates that this variant causes a significant decrease in SMAD3 structural stability (Qin BY et al. Genes Dev. 2002 Aug;16(15):1950-63; Ambry internal data). A different alteration located at the same position, resulting in the same protein change, c.733G>C (p.G245R), has been reported in an individual with aortic root dilation (Arroyave J et al. Cardiol Young, 2018;28:765-767). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26221609, 28185953, 35830949, 30661052, 29444731, 32917565, 24804794)

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
SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.	Hostetler EM	Journal of medical genetics	2019	PMID: 30661052
Isolated aortic dilation without osteoarthritis: a case of SMAD3 mutation.	Arroyave J	Cardiology in the young	2018	PMID: 29444731
Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition.	Aubart M	PloS one	2014	PMID: 24804794

Text-mined citations for rs863223737 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_005902.4(SMAD3):c.733G>A (p.Gly245Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs863223737 ...