Submissions for variant NM_000138.5(FBN1):c.3674C>T (p.Pro1225Leu)

gnomAD frequency: 0.00001  dbSNP: rs775532488

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815665	SCV000956128	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191877	SCV001359794	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1225 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 not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 6/251474 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.
Ambry Genetics	RCV001191877	SCV002619136	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-05-14	criteria provided, single submitter	clinical testing	The p.P1225L variant (also known as c.3674C>T), located in coding exon 29 of the FBN1 gene, results from a C to T substitution at nucleotide position 3674. The proline at codon 1225 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an adolescent idiopathic scoliosis cohort with limited clinical details (Buchan JG et al. Hum Mol Genet, 2014 Oct;23:5271-82). This amino acid position is poorly 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.
All of Us Research Program, National Institutes of Health	RCV004001782	SCV004814784	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1225 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 not been reported in individuals affected with Marfan syndrome or cardiovascular disorders in the literature, but it has been observed in an individual with adolescent idiopathic scoliosis (PMID: 24833718). This variant has been identified in 6/251474 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.
CeGaT Center for Human Genetics Tuebingen	RCV004546565	SCV005041910	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FBN1: PS4:Supporting