Submissions for variant NM_005359.6(SMAD4):c.728_735del (p.Gly243fs)

dbSNP: rs1060500742

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230766	SCV000543755	pathogenic	Juvenile polyposis syndrome	2021-01-28	criteria provided, single submitter	clinical testing	This sequence change deletes 8 nucleotides from exon 6 of the SMAD4 mRNA (c.728_735del), causing a frameshift at codon 243. This creates a premature translational stop signal (p.Gly243Alafs*18) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD4 are known to be pathogenic. This particular variant has been reported in individuals affected with an overlapping spectrum of juvenile polyposis and hereditary hemorrhagic telangiectasia (PMID: 22331366). It is also known as c.724_731delTCAGGGCC in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000481914	SCV000567314	pathogenic	not provided	2015-07-20	criteria provided, single submitter	clinical testing	The c.728_735delGGCCTCAG deletion in the SMAD4 gene has been reported previouslyin two patients with combined juvenile polyposis syndrome and hereditary hemorrhagictelangiectasia (Schwenter et al., 2012). This deletion causes a frameshift starting withcodon Glycine 243, changes this amino acid to an Alanine residue and creates a prematureStop codon at position 18 of the new reading frame, denoted p.Gly243AlafsX18. It ispredicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. Therefore, we consider the c.728_735delGGCCTCAG deletion in SMAD4 to be a pathogenic variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481914	SCV001550406	uncertain significance	not provided		no assertion criteria provided	clinical testing