Submissions for variant NM_000138.5(FBN1):c.8579A>G (p.Asp2860Gly)

dbSNP: rs368599541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181638	SCV000233941	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing	The D2860G variant in the FBN1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D2860G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D2860G 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-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret D2860G as a variant of uncertain significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795064	SCV000934505	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-20	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 200137). This missense change has been observed in individual(s) with Marfan syndrome (Invitae). This variant is present in population databases (rs368599541, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2860 of the FBN1 protein (p.Asp2860Gly).
Johns Hopkins Genomics, Johns Hopkins University	RCV001261005	SCV001438389	uncertain significance	Marfan syndrome	2020-09-11	criteria provided, single submitter	clinical testing	This FBN1 variant is absent from a large population dataset and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The aspartic acid residue at this position is highly evolutionarily conserved across most species assessed. Due to insufficient evidence, we consider the clinical significance of c.8579A>G to be uncertain at this time.
Color Diagnostics, LLC DBA Color Health	RCV001526100	SCV001736376	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2860 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 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.
Fulgent Genetics, Fulgent Genetics	RCV002492802	SCV002782540	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	2021-08-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001261005	SCV004844880	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 2860 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 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.