Submissions for variant NM_000138.5(FBN1):c.359A>T (p.Asn120Ile)

dbSNP: rs753900024

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001186949	SCV001353564	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 120 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 cardiovascular disorders in the literature. This variant has been identified in 1/250786 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	RCV001186949	SCV002617368	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-10-16	criteria provided, single submitter	clinical testing	The p.N120I variant (also known as c.359A>T), located in coding exon 4 of the FBN1 gene, results from an A to T substitution at nucleotide position 359. The asparagine at codon 120 is replaced by isoleucine, an amino acid with dissimilar 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	RCV002480618	SCV002797038	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	2021-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003129729	SCV003805976	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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 (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003770088	SCV004571102	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004008644	SCV004823138	uncertain significance	Marfan syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 120 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 cardiovascular disorders in the literature. This variant has been identified in 1/250786 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.