This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Uncertain significance
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 3
- First in ClinVar:
- Feb 7, 2015
- Most recent Submission:
- Mar 26, 2023
- Last evaluated:
- Aug 22, 2022
- Accession:
- VCV000180526.5
- Variation ID:
- 180526
- Description:
- single nucleotide variant
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NM_005902.4(SMAD3):c.1129G>A (p.Val377Ile)
- Allele ID
- 178708
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 15q22.33
- Genomic location
- 15: 67187484 (GRCh38) GRCh38 UCSC
- 15: 67479822 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005902.4:c.1129G>A MANE Select NP_005893.1:p.Val377Ile missense NM_001145102.2:c.814G>A NP_001138574.1:p.Val272Ile missense NM_001145103.2:c.997G>A NP_001138575.1:p.Val333Ile missense NM_001145104.2:c.544G>A NP_001138576.1:p.Val182Ile missense NC_000015.10:g.67187484G>A NC_000015.9:g.67479822G>A NG_011990.1:g.126628G>A - Protein change
- V377I, V182I, V272I, V333I
- Other names
- -
- Canonical SPDI
- NC_000015.10:67187483:G:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- Trans-Omics for Precision Medicine (TOPMed) 0.00001
- The Genome Aggregation Database (gnomAD), exomes 0.00002
- The Genome Aggregation Database (gnomAD) 0.00001
- Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Exome Aggregation Consortium (ExAC) 0.00003
- Links
- ClinGen: CA020043
- dbSNP: rs730880216
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Uncertain significance | 1 | no assertion criteria provided | Oct 17, 2014 | RCV000157503.1 | |
| Uncertain significance | 2 | criteria provided, multiple submitters, no conflicts | Aug 22, 2022 | RCV000547199.5 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| SMAD3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
870 | 925 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Uncertain significance
(May 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001344235.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction tools and conservation analyses suggest that this variant may … (more)
This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Aug 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000658870.2
First in ClinVar: Dec 26, 2017 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the SMAD3 protein (p.Val377Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the SMAD3 protein (p.Val377Ile). This variant is present in population databases (rs730880216, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 180526). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD3 protein function. 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)
|
|
|
Uncertain significance
(Oct 17, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207248.1
First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015 |
Number of individuals with the variant: 1
|
Functional evidence
Help| 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. |
Citations for this variant
Help| There are no citations in ClinVar for this variation. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs730880216...
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 Mar 26, 2023