Submissions for variant NM_005359.6(SMAD4):c.181A>G (p.Ile61Val)

gnomAD frequency: 0.00001  dbSNP: rs1064794204

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480772	SCV000568184	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing	This variant is denoted SMAD4 c.181A>G at the cDNA level, p.Ile61Val (I61V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. SMAD4 Ile61Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). SMAD4 Ile61Val is located in the MH1 domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether SMAD4 Ile61Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000581125	SCV000686532	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 61 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251246 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635474	SCV000756888	likely benign	Juvenile polyposis syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764160	SCV000895162	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
Ambry Genetics	RCV002413323	SCV002710411	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2024-09-17	criteria provided, single submitter	clinical testing	The p.I61V variant (also known as c.181A>G), located in coding exon 1 of the SMAD4 gene, results from an A to G substitution at nucleotide position 181. The isoleucine at codon 61 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480772	SCV002774739	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235240	SCV003933804	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.181A>G (p.Ile61Val) results in a conservative amino acid change located in the MAD homology 1, Dwarfin-type (IPR003619) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251246 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.181A>G in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.