Submissions for variant NM_000138.5(FBN1):c.1265G>A (p.Gly422Glu)

gnomAD frequency: 0.00035  dbSNP: rs139968089

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590466	SCV000233986	uncertain significance	not provided	2018-08-31	criteria provided, single submitter	clinical testing	The G422E variant of uncertain significance in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, G422E does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, this variant is observed in 23/23,998 (0.1%) African alleles in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV001079545	SCV000283604	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855644	SCV000695451	uncertain significance	not specified	2019-04-16	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1265G>A (p.Gly422Glu) results in a non-conservative amino acid change in the encoded protein sequence. It is located outside of known functional domains such as EGF-like- or TB domains (InterPro). 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 8.1e-05 in 282580 control chromosomes, predominantly at a frequency of 0.00092 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1265G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Eurofins Ntd Llc (ga)	RCV000590466	SCV000704867	uncertain significance	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001182507	SCV000738817	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV001182507	SCV001347973	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-12-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590466	SCV001477805	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	The FBN1 c.1265G>A; p.Gly422Glu variant (rs139968089), to our knowledge, is not reported in the medical literature. The variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 200178) and is found in the African population with an allele frequency of 0.09% (23/24,922 alleles) in the Genome Aggregation Database. The glycine at codon 422 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Gly422Glu variant is uncertain at this time.
Revvity Omics, Revvity	RCV000590466	SCV003833983	uncertain significance	not provided	2020-04-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590466	SCV004041932	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	FBN1: BS1