Submissions for variant NM_000138.5(FBN1):c.4727T>C (p.Met1576Thr)

gnomAD frequency: 0.00018  dbSNP: rs776625874

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586729	SCV000233834	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Reported in at least two individuals with aortic dilation/dissection (PMID: 16220557, 19012347, 21883168), as well as individuals with a Marfan-related phenotype (PMID: 31211626, 31163209); Reported in individuals with severe adolescent idiopathic scoliosis (PMID: 24833718, 26333736); In silico analysis supports that this missense variant does not alter protein structure/function; 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 FBN-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 31211626, 26333736, 21883168, 19012347, 29935118, 31163209, 28659821, 12938084, 24833718, 16220557)
Invitae	RCV000226053	SCV000283630	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181531	SCV000539146	uncertain significance	not specified	2017-02-03	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 2 papers, associated with Marfan syndrome. It is present in one individual with isolated dilation of the ascending aorta and one with Marfan syndrome. It is classified in ClinVar with 2 stars as VUS by GeneDx and Invitae. The variant has a Max MAF in ExAC of 0.015% (10 alleles) and in gnomAD of 0.02% (31 alleles). Max prevalence of Marfan is 1/3000. This AA is not conserved and Zebra Finch has a Thr at this position.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181531	SCV000695549	uncertain significance	not specified	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4727T>C (p.Met1576Thr) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 252050 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4727T>C has been reported in the literature in at least one individual with an unknown bicuspid aortic valve phenotype (e.g. Gillis_2017). The variant has also been reported in the literature in individuals with Adolescent Idiopathic Scoliosis and suspected Marfan Syndrome (e.g. Rommel_2005, Rybczynski_2008, Sheikhzadeh_2012, Buchan_2014, Madar_2019, Damrauer_2019). Several of the individuals described in these reports underwent clinical genetics evaluations and had a normal range of Ghent systemic features (4 to 5 points, e.g. Buchan_2014, Madar_2019) or were reported without cardiac involvement (e.g. Damrauer_2019). The patients described by Buchan et al. were reported to have normal echocardiograms and ophthalmological evaluations, and no family history of aortic aneurysm or scoliosis, therefore suggesting possible lack of co-segregation with disease. These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24833718, 31211626, 28659821, 26333736, 31163209, 16220557, 19012347, 21883168). Eight ClinVar submitters (evaluation after 2014) have cited the variant; seven submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV000778032	SCV000738748	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-06-11	criteria provided, single submitter	clinical testing	The p.M1576T variant (also known as c.4727T>C), located in coding exon 37 of the FBN1 gene, results from a T to C substitution at nucleotide position 4727. The methionine at codon 1576 is replaced by threonine, an amino acid with similar properties, and is located in the TGFBP #04 domain. This alteration has been detected in individuals reported to have isolated aortic dilation (Rommel K et al. Hum Mutat. 2005;26:529-39; Sheikhzadeh S et al. Clin Genet. 2012;82:240-7). This alteration was also detected in patients from an adolescent idiopathic scoliosis cohort, in which one individual also carried a variant in FBN2; however, these individuals did not meet diagnostic criteria for Marfan syndrome (Buchan JG et al. Hum Mol Genet. 2014;23:5271-82). This alteration has also been reported in subjects who did not have evidence of cardiovascular disease (Damrauer SM et al. Circ Genom Precis Med, 2019 06;12:e002454). This amino acid position is poorly 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.
Fulgent Genetics, Fulgent Genetics	RCV000765220	SCV000896456	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	2022-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778032	SCV000914144	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1576 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome and in an individual who presented with isolated dilatation of the ascending aorta (PMID: 16220557), as well as in an individual affected with suspected Marfan syndrome or related fibrillinopathy (PMID: 31163209). This variant has been identified in three individuals affected with idiopathic scoliosis, one of whom was studied in detail and did not show symptoms associated with Marfan syndrome (PMID: 24833718). This variant has also been identified in 34/282694 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000586729	SCV001716230	uncertain significance	not provided	2020-02-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000778032	SCV003838350	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955106	SCV004770197	uncertain significance	FBN1-related condition	2024-01-03	criteria provided, single submitter	clinical testing	The FBN1 c.4727T>C variant is predicted to result in the amino acid substitution p.Met1576Thr. This variant has been reported in the heterozygous state in patients with aortic dissection/dilation (Rommel et al. 2005. PubMed ID: 16220557 and Sheikhzadeh et al. 2012. PubMed ID: 21883168), an individual undergoing testing for suspected Marfan syndrome (Rybczynski et al. 2008. PubMed ID: 19012347), as well as patients with adolescent idiopathic scoliosis (Buchan et al. 2014. PubMed ID: 24833718 and Haller et al. 2015. PubMed ID: 26333736). To our knowledge, no functional studies were performed to help assess the pathogenicity of this variant. This variant has been documented in 34 heterozygous individuals in gnomAD and was interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/200054/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.