Submissions for variant NM_000138.5(FBN1):c.466A>C (p.Asn156His)

gnomAD frequency: 0.00005  dbSNP: rs746352371

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001170330	SCV000738921	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-04	criteria provided, single submitter	clinical testing	The p.N156H variant (also known as c.466A>C), located in coding exon 5 of the FBN1 gene, results from an A to C substitution at nucleotide position 466. The asparagine at codon 156 is replaced by histidine, an amino acid with similar properties, and is located in the EGF-like #03 domain. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821603	SCV000962368	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 156 of the FBN1 protein (p.Asn156His). This variant is present in population databases (rs746352371, gnomAD 0.004%). 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: 519790). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170330	SCV001332901	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170330	SCV001357078	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 156 of the FBN1 protein. Computational prediction tool indicates that this variant may have a deleterious impact on protein structure and function. 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 6/282716 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	RCV001567760	SCV001791505	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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; 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084)
Fulgent Genetics, Fulgent Genetics	RCV002499004	SCV002781840	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	2021-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002730	SCV004823132	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 156 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 cardiovascular disorders in the literature. This variant has been identified in 6/282716 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.