Submissions for variant NM_000138.5(FBN1):c.6707A>G (p.Tyr2236Cys)

dbSNP: rs368439899

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311146	SCV000320240	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-09-14	criteria provided, single submitter	clinical testing	The p.Y2236C variant (also known as c.6707A>G), located in coding exon 54 of the FBN1 gene, results from an A to G substitution at nucleotide position 6707. The tyrosine at codon 2236 is replaced by cysteine, an amino acid with highly dissimilar 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 6494 samples (12988 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.
GeneDx	RCV003238751	SCV003936445	likely pathogenic	not provided	2023-06-26	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 supports that this missense variant has a deleterious effect on protein structure/function; Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; 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); This variant is associated with the following publications: (PMID: 12938084, 10486319)
NHS Central & South Genomic Laboratory Hub	RCV005252844	SCV005907235	pathogenic	Thoracic aortic aneurysm or dissection	2025-04-09	criteria provided, single submitter	clinical testing
Department of Laboratory Medicine and Genetics, Samsung Medical Center	RCV005049504	SCV005684912	pathogenic	Marfan syndrome	2025-01-02	no assertion criteria provided	clinical testing	The NM_000138.5:c.6707A>G is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains. This variant was found in a patient with Marfan syndrome meeting revised Ghent criteria (aortic root dilatation, ectopia lentis, and a systemic score of 7 points) (Samsung Medical Center internal data). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PM1, PP2, PP3, PP4 with weighted strength, PM2_P).