Submissions for variant NM_000138.5(FBN1):c.2075T>A (p.Phe692Tyr)

gnomAD frequency: 0.00004  dbSNP: rs955639059

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001181544	SCV000738928	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-26	criteria provided, single submitter	clinical testing	The p.F692Y variant (also known as c.2075T>A), located in coding exon 16 of the FBN1 gene, results from a T to A substitution at nucleotide position 2075. The phenylalanine at codon 692 is replaced by tyrosine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species, and tyrosine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health	RCV001181544	SCV001346718	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 692 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 2/282838 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	RCV001591387	SCV001826915	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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)
Fulgent Genetics, Fulgent Genetics	RCV002477357	SCV002792525	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	2021-09-03	criteria provided, single submitter	clinical testing
Invitae	RCV002531822	SCV003262115	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002731	SCV004814925	uncertain significance	Marfan syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with tyrosine at codon 692 of the FBN1 protein. Computational prediction tool 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/282838 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.