Submissions for variant NM_000138.5(FBN1):c.7082C>T (p.Ser2361Leu)

gnomAD frequency: 0.00001  dbSNP: rs397515844

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035263	SCV000058910	uncertain significance	not specified	2009-07-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054041	SCV001218334	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2361 of the FBN1 protein (p.Ser2361Leu). This variant is present in population databases (rs397515844, gnomAD 0.002%). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 24793577). ClinVar contains an entry for this variant (Variation ID: 42418). 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) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. This variant disrupts the p.Ser2361 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 24793577; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
GeneDx	RCV001559901	SCV001782218	uncertain significance	not provided	2020-10-02	criteria provided, single submitter	clinical testing	Reported in a patient with TAAD (Lerner-Ellis et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42418; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24793577)
Ambry Genetics	RCV002362614	SCV002664025	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-17	criteria provided, single submitter	clinical testing	The p.S2361L variant (also known as c.7082C>T), located in coding exon 57 of the FBN1 gene, results from a C to T substitution at nucleotide position 7082. The serine at codon 2361 is replaced by leucine, an amino acid with dissimilar properties, and is located in the TGFBP #07 domain. This alteration was detected in one individual with TAAD (thoracic ascending aortic aneurysms and dissections) symptoms (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002504872	SCV002814060	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	2021-10-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035263	SCV003800649	uncertain significance	not specified	2024-06-18	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7082C>T (p.Ser2361Leu) results in a non-conservative amino acid change located in the one of the TGF-beta binding (TB) domains (IPR017878, UniProt) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250804 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7082C>T has been reported in the literature in an individual affected with (suspected) TAAD (Thoracic Aortic Aneurysms and Dissections), however no further phenotype details or co-segregation data were provided (Lerner-Ellis_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent study combining ACMG criteria with FBN1 gene-specific knowledge (i.e. considering critical FBN1 regions and appropriate minor allele frequency (MAF) cutoffs), classified the variant as VUS (Baudhuin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24793577, 31227806). ClinVar contains an entry for this variant (Variation ID: 42418). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV002362614	SCV004357326	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2361 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 been reported in an individual affected with thoracic aortic aneurysms and dissections (PMID: 24793577). This variant has been identified in 2/250804 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.