Submissions for variant NM_000138.5(FBN1):c.2228G>A (p.Arg743His)

gnomAD frequency: 0.00001  dbSNP: rs761942436

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507032	SCV000603659	uncertain significance	not specified	2017-03-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176834	SCV001340895	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 743 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 5/282808 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg743Cys, is thought to be disease-causing (ClinVar variation ID: 199993). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857268	SCV002182977	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481638	SCV002781356	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	2021-09-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001176834	SCV003863101	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-08	criteria provided, single submitter	clinical testing	The p.R743H variant (also known as c.2228G>A), located in coding exon 18 of the FBN1 gene, results from a G to A substitution at nucleotide position 2228. The arginine at codon 743 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004535641	SCV004113074	uncertain significance	FBN1-related disorder	2022-08-29	criteria provided, single submitter	clinical testing	The FBN1 c.2228G>A variant is predicted to result in the amino acid substitution p.Arg743His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48789528-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003558	SCV004814907	uncertain significance	Marfan syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 743 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 5/282808 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg743Cys, is thought to be disease-causing (ClinVar variation ID: 199993). 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	RCV004722847	SCV005333555	uncertain significance	not provided	2023-08-18	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; This variant is associated with the following publications: (PMID: 31227806)