Submissions for variant NM_000138.5(FBN1):c.353A>G (p.His118Arg)

gnomAD frequency: 0.00001  dbSNP: rs765503809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181646	SCV000233949	uncertain significance	not provided	2014-01-11	criteria provided, single submitter	clinical testing	p.His118Arg (CAC>CGC): c.353 A>G in exon 5 of the FBN1 gene (NM_000138.4)The H118R variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The H118R variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The H118 residue is conserved in mammals, and in silico analysis predicts H118R is benign to the protein structure/function. However, mutations in nearby residues (S115C, R122C) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. In addition, the H118R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if H118R is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001181847	SCV001347088	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 118 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 FBN1-related disorders in the literature. This variant has been identified in 9/250626 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236065	SCV001408777	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492803	SCV002775725	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	2021-10-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996702	SCV004823139	uncertain significance	Marfan syndrome	2023-04-24	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces histidine with arginine at codon 118 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/245356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Ambry Genetics	RCV001181847	SCV005032472	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-02-01	criteria provided, single submitter	clinical testing	The p.H118R variant (also known as c.353A>G), located in coding exon 4 of the FBN1 gene, results from an A to G substitution at nucleotide position 353. The histidine at codon 118 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.