Submissions for variant NM_005359.6(SMAD4):c.1546C>T (p.Gln516Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002403263	SCV002706297	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The p.Q516* variant (also known as c.1546C>T), located in coding exon 11 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1546. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This alteration occurs at the 3' terminus of theSMAD4 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 37 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this alteration disrupts a significant portion of the structure (Ambry internal data). This variant has been identified in an individual who met clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) and had a family history of HHT/juvenile polyposis syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004059035	SCV004932645	pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-02-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.