Submissions for variant NM_000138.5(FBN1):c.1042C>T (p.Gln348Ter)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254731	SCV000322366	pathogenic	not provided	2020-06-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16222657, 24941995, 18435798)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778876	SCV002014856	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1042C>T (p.Gln348X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251352 control chromosomes (gnomeAD). c.1042C>T has been reported in the literature in individuals affected with Marfan Syndrome (example, Arbustini_2005, Attanasio_2008, and Mariucci_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798764	SCV002041948	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-09-26	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272198	SCV002556516	pathogenic	Marfan syndrome	2022-01-07	criteria provided, single submitter	clinical testing

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