Submissions for variant NM_000138.5(FBN1):c.6416A>G (p.His2139Arg)

gnomAD frequency: 0.00001  dbSNP: rs794728248

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588265	SCV000233868	uncertain significance	not provided	2016-01-11	criteria provided, single submitter	clinical testing	The H2139R variant has not been published as a pathogenic variant or been reported as a benign polymorphism to our knowledge. The H2139R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammalian species within the EGF-like 36 calcium-binding domain of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, missense mutations in nearby residues (E2130K, V2136D, G2140R, G2140E, C2142Y) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. Furthermore, the H2139R 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.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588265	SCV000695581	uncertain significance	not provided	2016-08-26	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.6416A>G (p.His2139Arg) variant located in the EGF-like 36 calcium-binding domain causes a missense change involving a conserved nucleotide with 3/5 in silico tools predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. A clinical laboratory has cited the variant as "uncertain significance." Therefore, due to limited available information (ie, lack of clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241081	SCV001414074	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2139 of the FBN1 protein (p.His2139Arg). This variant is present in population databases (rs794728248, gnomAD 0.002%). 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: 200082). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. 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	RCV001525697	SCV001735877	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 2139 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 individual affected with pediatric myocarditis and dilated cardiomyopathy (PMID: 35877578). This variant has been identified in 2/250946 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.
Fulgent Genetics, Fulgent Genetics	RCV002503705	SCV002815213	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	2022-02-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996693	SCV004822445	uncertain significance	Marfan syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 2139 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 individual affected with pediatric myocarditis and dilated cardiomyopathy (PMID: 35877578). This variant has been identified in 2/250946 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.