Submissions for variant NM_000138.5(FBN1):c.6534T>A (p.Asn2178Lys)

gnomAD frequency: 0.00002  dbSNP: rs770257902

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001186064	SCV000738911	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-07-11	criteria provided, single submitter	clinical testing	The p.N2178K variant (also known as c.6534T>A), located in coding exon 53 of the FBN1 gene, results from a T to A substitution at nucleotide position 6534. The asparagine at codon 2178 is replaced by lysine, an amino acid with similar properties. This alteration was reported in an individual with adolescent idiopathic scoliosis (Buchan JG et al. Hum. Mol. Genet., 2014 Oct;23:5271-82). 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.
Blueprint Genetics	RCV000788251	SCV000927302	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797077	SCV000936617	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2178 of the FBN1 protein (p.Asn2178Lys). This variant is present in population databases (rs770257902, gnomAD 0.002%). This missense change has been observed in individual(s) with adolescent idiopathic scoliosis (PMID: 24833718). ClinVar contains an entry for this variant (Variation ID: 519782). 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 95%. 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	RCV001186064	SCV001352402	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 2178 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 been reported in one individual who was affected with adolescent idiopathic scoliosis but did not meet criteria for Marfan syndrome diagnosis (PMID: 24833718). This variant has been identified in 3/282550 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.
GeneDx	RCV000788251	SCV001787424	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Identified in an individual with adolescent idiopathic scoliosis in published literature who did not meet criteria for Marfan syndrome (Buchan et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 519782; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24833718)
Fulgent Genetics, Fulgent Genetics	RCV002483729	SCV002793997	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	2021-09-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001186064	SCV004240585	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-08-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002729	SCV004822441	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 2178 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 been reported in one individual who was affected with adolescent idiopathic scoliosis but did not meet criteria for Marfan syndrome diagnosis (PMID: 24833718). This variant has been identified in 3/282550 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.