Submissions for variant NM_000138.5(FBN1):c.4718C>T (p.Pro1573Leu)

gnomAD frequency: 0.00001  dbSNP: rs1286993730

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001191460	SCV001359282	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1573 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 cardiovascular disorders in the literature. This variant has been identified in 1/31402 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.
Fulgent Genetics, Fulgent Genetics	RCV002484049	SCV002777339	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	2021-08-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560113	SCV003478102	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-05-02	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with FBN1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 927888). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1573 of the FBN1 protein (p.Pro1573Leu).
All of Us Research Program, National Institutes of Health	RCV004010511	SCV004814701	uncertain significance	Marfan syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1573 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 cardiovascular disorders in the literature. This variant has been identified in 1/31402 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702681	SCV005203279	uncertain significance	not specified	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4718C>T (p.Pro1573Leu) results in a non-conservative amino acid change located in the TB domain (IPR017878) 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 251308 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.4718C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 927888). Based on the evidence outlined above, the variant was classified as uncertain significance.