Submissions for variant NM_000138.5(FBN1):c.6832C>G (p.Pro2278Ala)

dbSNP: rs363835

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422176	SCV000518178	likely benign	not specified	2016-09-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632048	SCV000753151	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-06	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659570	SCV000781405	uncertain significance	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769626	SCV000901024	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769626	SCV001356381	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422176	SCV001362384	likely benign	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6832C>G (p.Pro2278Ala) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251282 control chromosomes, predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 15.11 fold of 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 or African-American origin. c.6832C>G has been reported in the literature in at least one individual affected with clinical features of FBN1-related conditions (Gillis_2017). However, this report does not provide unequivocal conclusions about association of the variant with FBN1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28659821). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters reported the variant as a variant of uncertain significance, while four reported it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810910	SCV001473513	likely benign	not provided	2020-04-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000659570	SCV004822428	likely benign	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530565	SCV004728049	likely benign	FBN1-related disorder	2022-11-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).