ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7598A>G (p.Asn2533Ser)

gnomAD frequency: 0.00001  dbSNP: rs111231879
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181606 SCV000233909 uncertain significance not provided 2022-09-13 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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; 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)
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659580 SCV000781417 uncertain significance Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000799932 SCV000939621 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-01-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390452 SCV002675232 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-10-07 criteria provided, single submitter clinical testing The p.N2533S variant (also known as c.7598A>G), located in coding exon 61 of the FBN1 gene, results from an A to G substitution at nucleotide position 7598. The asparagine at codon 2533 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114329 SCV003800650 uncertain significance not specified 2023-01-09 criteria provided, single submitter clinical testing Variant summary: FBN1 c.7598A>G (p.Asn2533Ser) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250664 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7598A>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV000659580 SCV004836124 uncertain significance Marfan syndrome 2024-01-11 criteria provided, single submitter clinical testing

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