Submissions for variant NM_000138.5(FBN1):c.2893G>A (p.Glu965Lys)

dbSNP: rs748905831

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519986	SCV000617911	uncertain significance	not provided	2022-09-08	criteria provided, single submitter	clinical testing	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	RCV001176836	SCV001340897	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 965 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 FBN1-related disorders in the literature. This variant has been identified in 1/251442 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176836	SCV002041965	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527584	SCV003242347	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-18	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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 449603). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 965 of the FBN1 protein (p.Glu965Lys).
All of Us Research Program, National Institutes of Health	RCV001089767	SCV004814860	uncertain significance	Marfan syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 965 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 been identified in 1/251442 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV001089767	SCV001192854	likely pathogenic	Marfan syndrome	2015-08-26	no assertion criteria provided	clinical testing