Submissions for variant NM_000138.5(FBN1):c.2148A>G (p.Gly716=)

gnomAD frequency: 0.00042  dbSNP: rs141039922

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507578	SCV000603637	likely benign	not specified	2016-10-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727005	SCV000704864	uncertain significance	not provided	2017-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001188645	SCV000738788	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2016-04-26	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.
Invitae	RCV001089320	SCV000753161	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507578	SCV000917358	benign	not specified	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2148A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 12-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.2148A>G, has been reported in the literature in individuals affected with Marfan Syndrome (Comeglio_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "benign/likely benign" (3x) and "uncertain significance" (1x). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001188645	SCV001355733	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000727005	SCV001934981	likely benign	not provided	2019-03-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17657824)
All of Us Research Program, National Institutes of Health	RCV004003555	SCV004814915	benign	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing