Submissions for variant NM_000138.5(FBN1):c.2093C>T (p.Pro698Leu)

gnomAD frequency: 0.00002  dbSNP: rs764827921

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001184007	SCV000319951	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-08-14	criteria provided, single submitter	clinical testing	The p.P698L variant (also known as c.2093C>T), located in coding exon 16 of the FBN1 gene, results from a C to T substitution at nucleotide position 2093. The proline at codon 698 is replaced by leucine, an amino acid with a few similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631931	SCV000753034	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184007	SCV001349875	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 698 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 with thoracic aortic aneurysm and dissection, who showed no features of Marfan syndrome and lacked family history of Marfan syndrome (PMID: 26621581). This variant has been identified in 4/282774 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264433	SCV001442578	uncertain significance	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2093C>T (p.Pro698Leu) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2093C>T has been reported in the literature in an individual affected with a type A dissection, ascending aortic dilatation and other risk factors (bicuspid aortic valve and hypertension). But the variant did not segregate with aortic disease (Regalado_2016). This report however, does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001753735	SCV001988134	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Identified in a patient with Type A aortic dissection in the published literature (Regalado et al., 2015); however, this patient had other risk factors for dissection including bicuspid aortic valve and hypertension and the authors report this variant did not segregate with aortic disease; Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 26621581)
All of Us Research Program, National Institutes of Health	RCV003995716	SCV004814922	uncertain significance	Marfan syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 698 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 with thoracic aortic aneurysm and dissection, who showed no features of Marfan syndrome and lacked family history of Marfan syndrome (PMID: 26621581). This variant has been identified in 4/282774 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.
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755195	SCV000883024	likely benign	Congenital aneurysm of ascending aorta; Acute aortic dissection	2016-01-20	no assertion criteria provided	research