Submissions for variant NM_000138.5(FBN1):c.6819G>A (p.Met2273Ile)

gnomAD frequency: 0.00003  dbSNP: rs778027769

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522487	SCV000619292	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1-gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632028	SCV000753131	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-03	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680520	SCV000807912	uncertain significance	Marfan syndrome	2018-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188647	SCV001355736	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-11-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000522487	SCV001746220	uncertain significance	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001188647	SCV002664168	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226317	SCV003922531	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6819G>A (p.Met2273Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251276 control chromosomes (gnomAD). 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.6819G>A in individuals affected with Marfan 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 VUS (n=3) and benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.