Submissions for variant NM_000138.5(FBN1):c.1571C>T (p.Thr524Met)

gnomAD frequency: 0.00014  dbSNP: rs370575495

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216459	SCV000271779	uncertain significance	not specified	2015-02-03	criteria provided, single submitter	clinical testing	The p.Thr524Met variant in FBN1 has not been previously reported in individuals with Marfan syndrome, but has been identified in 2/11530 Latino chromosomes and 1/10406 African American chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370575495). Computational prediction to ols and conservation analysis suggest that the p.Thr524Met variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Thr524Met variant is unce rtain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216459	SCV000695459	likely benign	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1571C>T (p.Thr524Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 1613840 control chromosomes, predominantly at a frequency of 0.00037 within the African or African-American subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1571C>T has been reported in the literature in individuals affected with Cardiomyopathy (Richard_2019) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30471092). ClinVar contains an entry for this variant (Variation ID: 228683). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001180053	SCV001344902	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 524 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 19/282692 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001296986	SCV001485965	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494568	SCV002792303	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	2021-11-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997738	SCV004823045	uncertain significance	Marfan syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 524 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 19/282692 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	RCV001180053	SCV005113141	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-29	criteria provided, single submitter	clinical testing	The p.T524M variant (also known as c.1571C>T), located in coding exon 12 of the FBN1 gene, results from a C to T substitution at nucleotide position 1571. The threonine at codon 524 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.