Submissions for variant NM_000138.5(FBN1):c.7496T>C (p.Leu2499Pro)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226640	SCV003922530	uncertain significance	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7496T>C (p.Leu2499Pro) results in a non-conservative amino acid change located in an EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251208 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7496T>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003779808	SCV004588737	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-05	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2501043). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individuals with FBN1-related conditions (Invitae; external communication). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2499 of the FBN1 protein (p.Leu2499Pro). This variant is not present in population databases (gnomAD no frequency).
All of Us Research Program, National Institutes of Health	RCV004009680	SCV004833761	uncertain significance	Marfan syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 2499 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 not been identified 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	RCV004721167	SCV005326811	uncertain significance	not provided	2024-01-10	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; 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084)