Submissions for variant NM_000138.5(FBN1):c.5142G>A (p.Met1714Ile)

gnomAD frequency: 0.00001  dbSNP: rs368287795

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229864	SCV000283634	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-11-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001189722	SCV000317700	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-04-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001189722	SCV001357072	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1714 of the FBN1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. 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 4/251338 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.
GeneDx	RCV001572135	SCV001796722	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with an FBN1-related disorder to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1 related disorders (PMID: 12938084); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 30019023, 31227806)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001572135	SCV002049606	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing	The FBN1 c.5142G>A; p.Met1714Ile variant (rs368287795), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 237096). This variant is found in the general population with an allele frequency of 0.0016% (4/251338 alleles) in the Genome Aggregation Database. The methionine at codon 1714 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.511). However, given the lack of clinical and functional data, the significance of the p.Met1714Ile variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155134	SCV003844378	uncertain significance	not specified	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.5142G>A (p.Met1714Ile) results in a conservative amino acid change located in the TB5 region (Sun_2020) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 1613998 control chromosomes (gnomAD database v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome (2.7e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5142G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33030311). ClinVar contains an entry for this variant (Variation ID: 237096). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000663764	SCV004814672	uncertain significance	Marfan syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1714 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 cardiovascular disorders in the literature. This variant has been identified in 4/251338 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051766	SCV005685512	uncertain significance	Marfan syndrome; Progeroid and marfanoid aspect-lipodystrophy syndrome	2024-07-05	criteria provided, single submitter	clinical testing	The FBN1 c.5142G>A (p.Met1714Ile) variant, to our knowledge, has not been reported in the medical literature associated with patients with FBN1-related phenotypes. This variant has been reported in the ClinVar database as a variant of uncertain significance by six submitters and as a likely benign variant by two submitters (Variation ID: 237096). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.0026% in the European non-Finnish population which is lower than the incidence of Marfan syndrome. Computational predictors are uncertain as to the impact of this variant on FBN1 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Center for Medical Genetics Ghent, University of Ghent	RCV000663764	SCV000787113	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing