Submissions for variant NM_000138.5(FBN1):c.4895G>A (p.Arg1632His)

gnomAD frequency: 0.00001  dbSNP: rs756227025

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170539	SCV001333125	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170539	SCV001342812	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1632 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 been reported in an East Asian individual affected with Marfan syndrome, including ocular features without cardiovascular or skeletal features (PMD: 19839986). This variant has also been identified in 8/282728 chromosomes (8/19950 East Asian 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	RCV001170539	SCV002638871	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-21	criteria provided, single submitter	clinical testing	The p.R1632H variant (also known as c.4895G>A), located in coding exon 39 of the FBN1 gene, results from a G to A substitution at nucleotide position 4895. The arginine at codon 1632 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an individual suspected to have Marfan syndrome (Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67). This amino acid position is not well 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	RCV002559635	SCV003292900	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-09-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000274	SCV004814689	uncertain significance	Marfan syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1632 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 been reported in an East Asian individual affected with Marfan syndrome, including ocular features without cardiovascular or skeletal features (PMD: 19839986). This variant has also been identified in 8/282728 chromosomes (8/19950 East Asian 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.