Submissions for variant NM_000138.5(FBN1):c.8108G>T (p.Gly2703Val)

dbSNP: rs794728284

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181627	SCV000233930	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001181846	SCV001347087	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2703 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001181846	SCV002678844	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-26	criteria provided, single submitter	clinical testing	The p.G2703V variant (also known as c.8108G>T), located in coding exon 64 of the FBN1 gene, results from a G to T substitution at nucleotide position 8108. The glycine at codon 2703 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765121	SCV004590880	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2703 of the FBN1 protein (p.Gly2703Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200128). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003996699	SCV004844924	uncertain significance	Marfan syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2703 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783758	SCV005397639	uncertain significance	Weill-Marchesani syndrome 2, dominant	2023-11-10	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>T) at position 8108 of the coding sequence of the FBN1 gene that results in a glycine to valine amino acid change at residue 2703 of the fibrillin 1 protein. This is a previously reported variant (ClinVar 200128) that has not been observed in an individual affected by a FBN1-related disorder in the published literature, to our knowledge. This variant is absent from the gnomAD v4 population database (0/~1,614,000 alleles). Multiple bioinformatic tools predict that this Gly to Val amino acid change would be neutral, and the Gly2703 residue at this position is poorly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4, PM2, PP2