Submissions for variant NM_000138.5(FBN1):c.8299A>G (p.Asn2767Asp)

gnomAD frequency: 0.00004  dbSNP: rs771437236

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704657	SCV000833613	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2767 of the FBN1 protein (p.Asn2767Asp). This variant is present in population databases (rs771437236, gnomAD 0.02%). This missense change has been observed in individual(s) with Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 549458). 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 expected to disrupt FBN1 protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001180131	SCV001344998	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 2767 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/251334 chromosomes 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	RCV001180131	SCV002679266	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-28	criteria provided, single submitter	clinical testing	The p.N2767D variant (also known as c.8299A>G), located in coding exon 65 of the FBN1 gene, results from an A to G substitution at nucleotide position 8299. The asparagine at codon 2767 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002477477	SCV002793693	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV003235332	SCV003932946	uncertain significance	not provided	2023-11-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084)
CeGaT Center for Human Genetics Tuebingen	RCV003235332	SCV004129791	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	FBN1: PP2, BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001180131	SCV004240599	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000664018	SCV004844902	uncertain significance	Marfan syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 2767 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 10/251334 chromosomes 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000664018	SCV000787406	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing