Submissions for variant NM_000138.5(FBN1):c.6349A>G (p.Ile2117Val)

dbSNP: rs572754741

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190211	SCV001357654	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2117 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 1/250642 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	RCV001796381	SCV002032585	uncertain significance	not provided	2021-06-09	criteria provided, single submitter	clinical testing	Reported in an individual with acute aortic dissection (AAD) who underwent analysis of a panel of 69 AAD-associated genes (Zheng J et al. 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 30056620, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863015	SCV002222446	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538422	SCV004103557	uncertain significance	FBN1-related disorder	2022-12-22	criteria provided, single submitter	clinical testing	The FBN1 c.6349A>G variant is predicted to result in the amino acid substitution p.Ile2117Val. This variant was reported in an individual with aortic dissection and considered to be a variant of uncertain significance (Zheng et al 2018. PubMed ID: 30056620, supplemental table 2). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-48729549-T-C). 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	RCV004010417	SCV004822448	uncertain significance	Marfan syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2117 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 1/250642 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.