ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3400G>A (p.Gly1134Arg)

gnomAD frequency: 0.00001  dbSNP: rs372404949
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000817656 SCV000958233 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-12-23 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 660460). This missense change has been observed in individual(s) with clinical features of FBN1-related disease (Invitae). This variant is present in population databases (rs372404949, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1134 of the FBN1 protein (p.Gly1134Arg).
GeneDx RCV001772124 SCV001993960 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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).
Ambry Genetics RCV002453863 SCV002612650 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-05-31 criteria provided, single submitter clinical testing The p.G1134R variant (also known as c.3400G>A), located in coding exon 27 of the FBN1 gene, results from a G to A substitution at nucleotide position 3400. The glycine at codon 1134 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002487809 SCV002781053 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 2021-10-29 criteria provided, single submitter clinical testing

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