ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.8449T>G (p.Phe2817Val)

gnomAD frequency: 0.00001  dbSNP: rs148741353
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726402 SCV000233936 uncertain significance not provided 2024-06-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; 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 (PMID: 12938084); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12938084, 27906200)
Eurofins Ntd Llc (ga) RCV000726402 SCV000344403 uncertain significance not provided 2016-08-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000801911 SCV000941712 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-12-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408787 SCV002675996 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-09-06 criteria provided, single submitter clinical testing The p.F2817V variant (also known as c.8449T>G), located in coding exon 65 of the FBN1 gene, results from a T to G substitution at nucleotide position 8449. The phenylalanine at codon 2817 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in one individual from an FBN1-related database (Groth KA et al. Genet Med, 2017 07;19:772-777). This amino acid position is not well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782290 SCV005394350 uncertain significance not specified 2024-09-16 criteria provided, single submitter clinical testing Variant summary: FBN1 c.8449T>G (p.Phe2817Val) results in a non-conservative amino acid change in 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 2e-05 in 251424 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.8449T>G in individuals affected with Aortopathy or other FBN1-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 200132). Based on the evidence outlined above, the variant was classified as uncertain significance.

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