ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3759G>C (p.Gln1253His)

dbSNP: rs2141289701
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001368028 SCV001564404 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-04-27 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. This variant has not been reported in the literature in individuals with FBN1-related conditions. This sequence change replaces glutamine with histidine at codon 1253 of the FBN1 protein (p.Gln1253His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency).
All of Us Research Program, National Institutes of Health RCV004803670 SCV005424822 uncertain significance Marfan syndrome 2024-04-25 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 1253 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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.

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