Submissions for variant NM_000138.5(FBN1):c.6845G>A (p.Arg2282Gln)

gnomAD frequency: 0.00001  dbSNP: rs759696323

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527072	SCV000627976	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576458	SCV000678238	uncertain significance	Marfan syndrome	2017-08-01	criteria provided, single submitter	clinical testing	FBN1 NM_000138 exon 56 p.Arg2282Gln (c.6845G>A): This variant has not been previously reported in the literature but has been identified in 10/33554 Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs759696323). Computational predictive tools for this variant are unclear. However, this variant is present in 3 other species (Collared Flycatcher, Zebra Finch and Coelacanth), suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000772096	SCV000905131	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2282 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 21/251286 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	RCV001755802	SCV001985196	uncertain significance	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV000772096	SCV002666675	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-02-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002497067	SCV002815570	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	2021-12-27	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002497067	SCV003919942	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	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138 exon 56 p.Arg2282Gln (c.6845G>A): This variant has not been previously reported in the literature but has been identified in 10/33554 Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs759696323). Computational predictive tools for this variant are unclear. However, this variant is present in 3 other species (Collared Flycatcher, Zebra Finch and Coelacanth), suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV000576458	SCV004822423	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2282 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 21/251286 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.