ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1219G>C (p.Val407Leu)

gnomAD frequency: 0.00001  dbSNP: rs147621330
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000558005 SCV000632754 likely benign Juvenile polyposis syndrome 2024-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002311850 SCV000671973 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-06-01 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics RCV000764164 SCV000895166 uncertain significance Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000562603 SCV000910026 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 407 of the SMAD4 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 SMAD4-related disorders in the literature. This variant has been identified in 4/282846 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001662542 SCV001471767 uncertain significance not provided 2020-03-13 criteria provided, single submitter clinical testing The SMAD4 c.1219G>C; p.Val407Leu variant (rs147621330), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 460530). This variant is found on only four chromosomes (4/282846 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 407 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Val407Leu variant is uncertain at this time.
GeneDx RCV001662542 SCV001874863 uncertain significance not provided 2024-09-16 criteria provided, single submitter clinical testing 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; Observed in an individual with prostate cancer (PMID: 34326862); This variant is associated with the following publications: (PMID: 23718828, 34326862, 17873119, 18823382, 15235019)
AiLife Diagnostics, AiLife Diagnostics RCV001662542 SCV002503166 uncertain significance not provided 2021-12-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003476248 SCV004202586 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2024-03-05 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003476248 SCV004820083 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2024-04-16 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 407 of the SMAD4 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 SMAD4-related disorders in the literature. This variant has been identified in 4/282846 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.
True Health Diagnostics RCV000562603 SCV000788212 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing

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