ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6559G>A (p.Gly2187Ser)

gnomAD frequency: 0.00001  dbSNP: rs760055383
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192956 SCV001361435 uncertain significance not specified 2019-05-28 criteria provided, single submitter clinical testing Variant summary: FBN1 c.6559G>A (p.Gly2187Ser) results in a non-conservative amino acid change located in the EGF-like domain(IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251234 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6559G>A has been reported in the literature in an individual affected with acute aortic dissection who carries a likely pathogenic ACTA2 variant (Zheng_2018). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001812243 SCV001471125 uncertain significance not provided 2020-01-17 criteria provided, single submitter clinical testing The FBN1 c.6559G>A; p.Gly2187Ser variant (rs760055383) is reported in the literature in an individual affected with acute aortic dissection, but without a clear association with disease (Zheng 2018). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 2187 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Gly2187Ser variant is uncertain at this time. References: Zheng et al. Genetic diagnosis of acute aortic dissection in South China Han population using next-generation sequencing. Int J Legal Med. 2018 Sep;132(5):1273-1280.
Fulgent Genetics, Fulgent Genetics RCV002484059 SCV002798310 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 2022-01-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002559217 SCV003277909 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2187 of the FBN1 protein (p.Gly2187Ser). This variant is present in population databases (rs760055383, gnomAD 0.02%). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 30056620). ClinVar contains an entry for this variant (Variation ID: 928686). 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. This variant disrupts the p.Gly2187 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25944730), which suggests that this may be a clinically significant amino acid residue. 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 RCV004010603 SCV004824365 uncertain significance Marfan syndrome 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 2187 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 acute aortic dissection (PMID: 30056620). This variant has been identified in 3/251234 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.

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