Submissions for variant NM_000138.5(FBN1):c.4462G>T (p.Val1488Leu)

dbSNP: rs1566904712

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768216	SCV000898692	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 exon37 p.Val1488Leu (c.4462G>T): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical signifance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001191894	SCV001359819	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1488 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV003999915	SCV004814724	uncertain significance	Marfan syndrome	2024-01-03	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is located in the calcium-binding EGF-like motif 26 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 is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.