ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3592A>G (p.Ile1198Val)

gnomAD frequency: 0.00001  dbSNP: rs370572503
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001192260 SCV001360288 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-12-12 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 1198 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 3/251412 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 RCV001192260 SCV002613409 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-11-28 criteria provided, single submitter clinical testing The p.I1198V variant (also known as c.3592A>G), located in coding exon 29 of the FBN1 gene, results from an A to G substitution at nucleotide position 3592. The isoleucine at codon 1198 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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 RCV002484058 SCV002775075 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 2021-11-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002560148 SCV003033857 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-01-11 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 928399). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (rs370572503, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1198 of the FBN1 protein (p.Ile1198Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV004010589 SCV004814786 uncertain significance Marfan syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 1198 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

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