Submissions for variant NM_000138.5(FBN1):c.2773C>G (p.Leu925Val)

gnomAD frequency: 0.00001  dbSNP: rs149681175

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001180582	SCV000738865	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-01-12	criteria provided, single submitter	clinical testing	The p.L925V variant (also known as c.2773C>G), located in coding exon 23 of the FBN1 gene, results from a C to G substitution at nucleotide position 2773. The leucine at codon 925 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781376	SCV000919355	uncertain significance	not specified	2017-12-01	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.2773C>G (p.Leu925Val) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/246236 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001180582	SCV001345541	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 925 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 4/251424 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	RCV001558691	SCV001780693	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868123	SCV002147372	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483728	SCV002789983	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	2021-12-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001558691	SCV004702736	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FBN1: PP2, BP4, BS2
All of Us Research Program, National Institutes of Health	RCV004002724	SCV004814872	uncertain significance	Marfan syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 925 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 cardiovascular disorders in the literature. This variant has been identified in 4/251424 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.