Submissions for variant NM_005359.6(SMAD4):c.572C>T (p.Ser191Leu)

gnomAD frequency: 0.00001  dbSNP: rs752575871

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002327231	SCV001186477	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.S191L variant (also known as c.572C>T), located in coding exon 4 of the SMAD4 gene, results from a C to T substitution at nucleotide position 572. The serine at codon 191 is replaced by leucine, an amino acid with dissimilar 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.
Invitae	RCV001040401	SCV001203973	uncertain significance	Juvenile polyposis syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 191 of the SMAD4 protein (p.Ser191Leu). This variant is present in population databases (rs752575871, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 825928). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 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.
Color Diagnostics, LLC DBA Color Health	RCV001024458	SCV001356949	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 191 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 SMAD4-related disorders in the literature. This variant has been identified in 2/251486 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.
GeneDx	RCV003442150	SCV004169842	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a child with combined pituitary hormone deficiency who was also found to have a de novo loss-of-function variant in BMP4 (Rodrguez-Contreras et al., 2019); This variant is associated with the following publications: (PMID: 25769001, 15235019, 18823382, 22992590, 31120642)