Submissions for variant NM_000138.5(FBN1):c.8027C>T (p.Pro2676Leu)

gnomAD frequency: 0.00016  dbSNP: rs146469379

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483455	SCV000564996	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697974	SCV000826610	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765218	SCV000896454	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	2021-10-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180112	SCV001344975	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2676 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 11/281132 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	RCV001180112	SCV002675523	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-08-30	criteria provided, single submitter	clinical testing	The p.P2676L variant (also known as c.8027C>T), located in coding exon 63 of the FBN1 gene, results from a C to T substitution at nucleotide position 8027. The proline at codon 2676 is replaced by leucine, an amino acid with similar properties. This amino acid position is well 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	RCV004002242	SCV004844928	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 47 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/275450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.