Submissions for variant NM_000138.5(FBN1):c.484G>A (p.Ala162Thr)

gnomAD frequency: 0.00001  dbSNP: rs193922210

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	RCV000029745	SCV000052398	likely pathogenic	Marfan syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001189911	SCV001357296	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-09-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 162 of the FBN1 protein. Computational prediction tool 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). 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 1/31398 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	RCV001189911	SCV002639444	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-13	criteria provided, single submitter	clinical testing	The p.A162T variant (also known as c.484G>A), located in coding exon 5 of the FBN1 gene, results from a G to A substitution at nucleotide position 484. The alanine at codon 162 is replaced by threonine, an amino acid with similar properties, and is located in the EGF-like #03 domain. This alteration has been reported in association with Marfan syndrome (Groth KA et al. Genet. Med., 2017 07;19:772-777). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002513249	SCV003302850	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 162 of the FBN1 protein (p.Ala162Thr). This variant is present in population databases (rs193922210, gnomAD 0.007%). 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: 36083). 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.
GeneDx	RCV003148624	SCV003837519	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Reported in published literature but detailed clinical information is not provided (Groth et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27906200, 12938084, 31227806)
All of Us Research Program, National Institutes of Health	RCV000029745	SCV004823128	uncertain significance	Marfan syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 162 of the FBN1 protein. Computational prediction tool 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). 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 1/31398 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.