ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4312A>G (p.Ser1438Gly)

gnomAD frequency: 0.00001  dbSNP: rs1309215883
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001052579 SCV001216795 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-09-10 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 848754). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1438 of the FBN1 protein (p.Ser1438Gly). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194176 SCV001363510 uncertain significance not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4312A>G (p.Ser1438Gly) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251370 control chromosomes (gnomAD). 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.4312A>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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