The c.871+1G>A in SMAD3 has been reported in two apparently unrelated Cypriot families with autosomal dominant inheritance, segregated with the thoracic aortic aneurysm (TAA) on seven affected individuals and was absent from large population databases. mRNA analysis showed that this mutation (c.871+1G>A) disrupts normal splicing, leading to exon 6 skipping. According to the ACMG guidelines the c.871+1G>A variant can be classified as pathogenic with one Very Strong (PVS1), one Strong (PS3), one Moderate (PM2) and two Supporting (PP1 and PP3) evidences of pathogenicity.
ClinVar Genomic variation as it relates to human health
NM_005902.4(SMAD3):c.871+1G>A
Germline
Classification
Help
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.
(3)
Help
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
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005902.4(SMAD3):c.871+1G>A
Variation ID: 692110 Accession: VCV000692110.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q22.33 15: 67181454 (GRCh38) [ NCBI UCSC ] 15: 67473792 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 26, 2020 Jul 23, 2024 Oct 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005902.4:c.871+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001145102.2:c.556+1G>A splice donor NM_001145103.2:c.739+1G>A splice donor NM_001145104.2:c.286+1G>A splice donor NM_001407011.1:c.871+1G>A splice donor NM_001407012.1:c.739+1G>A splice donor NM_001407013.1:c.871+1G>A splice donor NM_001407014.1:c.724+1G>A splice donor NM_001407015.1:c.424+1G>A splice donor NM_001407016.1:c.556+1G>A splice donor NM_001407017.1:c.286+1G>A splice donor NM_005902.3:c.871+1G>A NC_000015.10:g.67181454G>A NC_000015.9:g.67473792G>A NG_011990.1:g.120598G>A NG_011990.2:g.120854G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000015.10:67181453:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| SMAD3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1042 | 1106 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2019 | RCV001027517.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 3, 2023 | RCV001869307.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 17, 2023 | RCV004594235.1 |
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. |
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Pathogenic
(Sep 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ascending aortic dissection
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Cardiovascular Genetics and the Laboratory of Forensic Genetics, Cyprus Institute of Neurology and Genetics
Accession: SCV000992602.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
Comment:
The c.871+1G>A in SMAD3 has been reported in two apparently unrelated Cypriot families with autosomal dominant inheritance, segregated with the thoracic aortic aneurysm (TAA) on … (more)
The c.871+1G>A in SMAD3 has been reported in two apparently unrelated Cypriot families with autosomal dominant inheritance, segregated with the thoracic aortic aneurysm (TAA) on seven affected individuals and was absent from large population databases. mRNA analysis showed that this mutation (c.871+1G>A) disrupts normal splicing, leading to exon 6 skipping. According to the ACMG guidelines the c.871+1G>A variant can be classified as pathogenic with one Very Strong (PVS1), one Strong (PS3), one Moderate (PM2) and two Supporting (PP1 and PP3) evidences of pathogenicity. (less)
Observation 1:
Number of individuals with the variant: 10
Number of families with the variant: 2
Clinical Features:
Ascending aortic dissection (present)
Zygosity: Single Heterozygote
Sex: mixed
Ethnicity/Population group: Cypriots
Geographic origin: Cyprus
Comment on evidence:
This variant was identified in 10 individuals but 7 out of 10 were diagnosed with TAA.
Observation 2:
Clinical Features:
Ascending aortic dissection (present)
Zygosity: Single Heterozygote
Age: 60-69 years
Sex: female
Ethnicity/Population group: Cypriots
Geographic origin: Cyprus
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Pathogenic
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002250822.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 32597575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 692110). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 32597575). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Aneurysm-osteoarthritis syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086362.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). Dominant negative is a suggested mechanism of disease in this gene for missense variants in the MH2 domain (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features of Loeys-Dietz syndrome associated with SMAD3 are variable, and the penetrance of aortic events generally increases with age (PMIDs: 20301312, 30661052). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR and Sanger sequencing analysis of an aortic tissue sample from a proband with this variant demonstrated exon 6 skipping. This exon skipping was expected to result in an in-frame deletion and cause protein misfolding (PMID: 32597575). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.871+1G>T and c.871+2T>C have been reported as likely pathogenic and pathogenic, respectively, by clinical testing laboratories (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in two apparently unrelated Cypriot families with nonsyndromic familial thoracic aortic aneurysm and dissection, including two family members with osteoarthritis and skeletal signs but without aortic dilatation or aneurysm reported (PMID: 32597575). It has also been reported in an individual with connective tissue disease findings whose brother also has this variant and required surgery for splenic aneurysm (PMID: 32897753). In addition, this variant has been reported as likely pathogenic by a clinical testing laboratory (ClinVar). A CNV analysis of targeted NGS (exome) data has detected a deletion of exon 6 in an individual with thoracic aortic aneurysm; however, the exact deletion breakpoints are not available (PMIDs: 29907982, 35031499). (SP) 0901 - This variant has strong evidence for segregation with disease. In one of the families with nonsyndromic familial thoracic aortic aneurysm and dissection published in the literature, this variant segregated with disease in a total of eight family members (PMID: 32597575). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Comment:
Comment:
This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 32597575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 692110). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 32597575). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). Dominant negative is a suggested mechanism of disease in this gene for missense variants in the MH2 domain (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features of Loeys-Dietz syndrome associated with SMAD3 are variable, and the penetrance of aortic events generally increases with age (PMIDs: 20301312, 30661052). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR and Sanger sequencing analysis of an aortic tissue sample from a proband with this variant demonstrated exon 6 skipping. This exon skipping was expected to result in an in-frame deletion and cause protein misfolding (PMID: 32597575). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.871+1G>T and c.871+2T>C have been reported as likely pathogenic and pathogenic, respectively, by clinical testing laboratories (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in two apparently unrelated Cypriot families with nonsyndromic familial thoracic aortic aneurysm and dissection, including two family members with osteoarthritis and skeletal signs but without aortic dilatation or aneurysm reported (PMID: 32597575). It has also been reported in an individual with connective tissue disease findings whose brother also has this variant and required surgery for splenic aneurysm (PMID: 32897753). In addition, this variant has been reported as likely pathogenic by a clinical testing laboratory (ClinVar). A CNV analysis of targeted NGS (exome) data has detected a deletion of exon 6 in an individual with thoracic aortic aneurysm; however, the exact deletion breakpoints are not available (PMIDs: 29907982, 35031499). (SP) 0901 - This variant has strong evidence for segregation with disease. In one of the families with nonsyndromic familial thoracic aortic aneurysm and dissection published in the literature, this variant segregated with disease in a total of eight family members (PMID: 32597575). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
sequence_variant_affecting_splicing
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Cardiovascular Genetics and the Laboratory of Forensic Genetics, Cyprus Institute of Neurology and Genetics
Accession: SCV000992602.1
|
|
Comment:
The c.871+1G>A in SMAD3 has been reported in two apparently unrelated Cypriot families with autosomal dominant inheritance, segregated with the thoracic aortic aneurysm (TAA) on seven affected individuals and was absent from large population databases. mRNA analysis showed that this mutation (c.871+1G>A) disrupts normal splicing, leading to exon 6 skipping. According to the ACMG guidelines the c.871+1G>A variant can be classified as pathogenic with one Very Strong (PVS1), one Strong (PS3), one Moderate (PM2) and two Supporting (PP1 and PP3) evidences of pathogenicity.
Comment:
This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 32597575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 692110). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 32597575). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). Dominant negative is a suggested mechanism of disease in this gene for missense variants in the MH2 domain (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features of Loeys-Dietz syndrome associated with SMAD3 are variable, and the penetrance of aortic events generally increases with age (PMIDs: 20301312, 30661052). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR and Sanger sequencing analysis of an aortic tissue sample from a proband with this variant demonstrated exon 6 skipping. This exon skipping was expected to result in an in-frame deletion and cause protein misfolding (PMID: 32597575). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0703 - Other canonical splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.871+1G>T and c.871+2T>C have been reported as likely pathogenic and pathogenic, respectively, by clinical testing laboratories (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in two apparently unrelated Cypriot families with nonsyndromic familial thoracic aortic aneurysm and dissection, including two family members with osteoarthritis and skeletal signs but without aortic dilatation or aneurysm reported (PMID: 32597575). It has also been reported in an individual with connective tissue disease findings whose brother also has this variant and required surgery for splenic aneurysm (PMID: 32897753). In addition, this variant has been reported as likely pathogenic by a clinical testing laboratory (ClinVar). A CNV analysis of targeted NGS (exome) data has detected a deletion of exon 6 in an individual with thoracic aortic aneurysm; however, the exact deletion breakpoints are not available (PMIDs: 29907982, 35031499). (SP) 0901 - This variant has strong evidence for segregation with disease. In one of the families with nonsyndromic familial thoracic aortic aneurysm and dissection published in the literature, this variant segregated with disease in a total of eight family members (PMID: 32597575). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Loeys-Dietz Syndrome. | Adam MP | - | 2024 | PMID: 20301312 |
| Neurovascular abnormalities in patients with Loeys-Dietz syndrome type III. | Dekker S | European journal of medical genetics | 2022 | PMID: 35031499 |
| Enrichment of Rare Variants in Loeys-Dietz Syndrome Genes in Spontaneous Coronary Artery Dissection but Not in Severe Fibromuscular Dysplasia. | Verstraeten A | Circulation | 2020 | PMID: 32897753 |
| Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports. | Keravnou A | Molecular genetics & genomic medicine | 2020 | PMID: 32597575 |
| 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 |
| Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. | Overwater E | Human mutation | 2018 | PMID: 29907982 |
Text-mined citations for rs1595956832 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.