ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4492A>G (p.Ile1498Val)

gnomAD frequency: 0.00001  dbSNP: rs761187818
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181523 SCV000233826 uncertain significance not provided 2023-03-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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 (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659544 SCV000781372 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001178818 SCV001343352 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 1498 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 not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 2/282494 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 RCV001312619 SCV001503079 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-12-06 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485195 SCV002778053 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 2021-09-30 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003996689 SCV004814722 uncertain significance Marfan syndrome 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 1498 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/282494 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 RCV001178818 SCV005585723 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-07-17 criteria provided, single submitter clinical testing The p.I1498V variant (also known as c.4492A>G), located in coding exon 36 of the FBN1 gene, results from an A to G substitution at nucleotide position 4492. The isoleucine at codon 1498 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV002485195 SCV006057761 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 2021-07-30 criteria provided, single submitter research

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