Submissions for variant NM_000138.5(FBN1):c.8311G>A (p.Val2771Ile)

gnomAD frequency: 0.00006  dbSNP: rs193922244

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029792	SCV000052446	likely benign	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8311G>A (p.Val2771Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.58 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 South Asian origin. To our knowledge, no occurrence of c.8311G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 36129). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000252734	SCV000319240	uncertain significance	Cardiovascular phenotype	2014-02-10	criteria provided, single submitter	clinical testing	The p.V2771I variant (also known as c.8311G>A), located in coding exon 65 of the FBN1 gene, results from a G to A substitution at nucleotide position 8311. The valine at codon 2771 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs193922244. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.01% (1/12,990), having been observed in 0.02% (1/4396) of African American alleles and in none of 8594 European American alleles. Based on protein sequence alignment, this amino acid position is not conserved in available vertebrate species, and isoleucine is the reference amino acid in several species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx	RCV000427863	SCV000536361	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN1 gene. The V2771I variant has not been published as pathogenic or been reported as benign to our knowledge. The V2771I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to valine are tolerated across species and where isoleucine is the wild type in multiple species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the V2771I variant 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). Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server).
Color Diagnostics, LLC DBA Color Health	RCV000777720	SCV000913665	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-08-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001306947	SCV001496335	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000427863	SCV004041929	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	FBN1: BP4