ClinVar Miner

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

gnomAD frequency: 0.00018  dbSNP: rs776625874
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586729 SCV000233834 uncertain significance not provided 2024-09-04 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 indicates 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, 24833718, 16220557, 28659821, 37937776, 12938084)
Labcorp Genetics (formerly Invitae), Labcorp 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 likely benign Familial thoracic aortic aneurysm and aortic dissection 2023-09-29 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.
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
All of Us Research Program, National Institutes of Health RCV003996692 SCV004814699 uncertain significance Marfan syndrome 2023-12-13 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 with unknown family history who presented with isolated dilatation of the ascending aorta (PMID: 16220557). This variant has also been identified in three individuals affected with idiopathic scoliosis (PMID: 24833718), one of whom was studied in detail and did not show symptoms associated with Marfan syndrome. This variant has been observed in an individual affected with suspected Marfan syndrome or related fibrillinopathy. 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.
PreventionGenetics, part of Exact Sciences RCV004539701 SCV004770197 uncertain significance FBN1-related disorder 2024-01-03 no assertion criteria provided 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.

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