ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3797A>T (p.Tyr1266Phe)

gnomAD frequency: 0.00001  dbSNP: rs200283837
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001183242 SCV000738823 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-11-22 criteria provided, single submitter clinical testing The p.Y1266F variant (also known as c.3797A>T), located in coding exon 30 of the FBN1 gene, results from an A to T substitution at nucleotide position 3797. The tyrosine at codon 1266 is replaced by phenylalanine, an amino acid with highly similar properties, and is located in the cb EGF-like #16 domain. This alteration was first reported in a study screening for FBN1 alterations, but no clinical detail was provided (Mátyás G et al. Hum. Mutat. 2002;19:443-56). This alteration was described in an individual with aortic dilatation and dissection, who also had a second FBN1 alteration (Regalado ES et al. Clin. Genet. 2016;89:719-23). This alteration has also been seen in another subject with ascending aortic aneurysm (Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This amino acid position is not well conserved in available vertebrate species, and phenylalanine is the reference amino acid in other 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756134 SCV000883855 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001183242 SCV001348923 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-12-02 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with phenylalanine at codon 1266 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 a family affected with familial thoracic aortic aneurysms and acute aortic dissections (PMID: 26621581). This variant has been identified in 14/251128 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 RCV001218747 SCV001390645 benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-11-27 criteria provided, single submitter clinical testing
GeneDx RCV000756134 SCV001793002 uncertain significance not provided 2022-11-14 criteria provided, single submitter clinical testing Observed in trans with another FBN1 variant in an individual with aortic root dilatation and aortic dissection (Regalado et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 24941995, 25812041, 25637381, 11933199, 27647783, 26621581, 29543232, 12938084)
All of Us Research Program, National Institutes of Health RCV000148489 SCV004814777 uncertain significance Marfan syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with phenylalanine at codon 1266 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 a family affected with familial thoracic aortic aneurysms and acute aortic dissections (PMID: 26621581). This variant has been identified in 14/251128 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.
CSER _CC_NCGL, University of Washington RCV000148489 SCV000190193 likely benign Marfan syndrome 2014-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000755197 SCV000883026 uncertain significance Congenital aneurysm of ascending aorta; Acute aortic dissection 2016-01-20 no assertion criteria provided research

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