ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.1129G>A (p.Val377Ile)

gnomAD frequency: 0.00001  dbSNP: rs730880216
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000547199 SCV000658870 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-08-04 criteria provided, single submitter clinical testing Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SMAD3 function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180526). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (Invitae). This variant is present in population databases (rs730880216, gnomAD 0.009%). 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).
Color Diagnostics, LLC DBA Color Health RCV000547199 SCV001344235 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 377 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD3-related disorders in the literature. This variant has been identified in 6/251488 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
All of Us Research Program, National Institutes of Health RCV003998342 SCV004815418 uncertain significance Aneurysm-osteoarthritis syndrome 2023-11-30 criteria provided, single submitter clinical testing 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.
Blueprint Genetics RCV000157503 SCV000207248 uncertain significance Arterial dissection; Cutaneous polyarteritis nodosa 2014-10-17 no assertion criteria provided clinical testing

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