ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1885G>A (p.Val629Ile)

gnomAD frequency: 0.00004  dbSNP: rs140503215
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001764800 SCV001989264 uncertain significance not provided 2024-04-15 criteria provided, single submitter clinical testing Has been reported in an individual with hereditary thoracic aortic disease (H-TAD) (PMID: 29907982); In silico analysis supports that this missense variant does not alter protein structure/function; 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 (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084, 29907982)
Fulgent Genetics, Fulgent Genetics RCV002488525 SCV002786297 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 2021-09-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002538760 SCV003010790 benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-11-18 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004008989 SCV004818607 uncertain significance Marfan syndrome 2023-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004801043 SCV005422032 uncertain significance not specified 2024-10-28 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1885G>A (p.Val629Ile) 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 1.6e-05 in 251446 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1885G>A has been reported in the literature in individuals affected with Thoracic aortic disorder (Overwater_2018). These report(s) do 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. The following publication have been ascertained in the context of this evaluation (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 1303684). Based on the evidence outlined above, the variant was classified as uncertain significance.

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