ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.362A>G (p.Asp121Gly) (rs770483769)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250915 SCV000319964 uncertain significance Cardiovascular phenotype 2015-08-12 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.
GeneDx RCV000493996 SCV000582740 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The D121G variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by another clinical laboratory in association with TAAD (ClinVar SCV000319964.1; Landrum et al., 2016). The D121G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, D121G does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009). Finally, D121G has been observed in 3/66408 (0.005%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV001323582 SCV001514505 uncertain significance Congenital contractural arachnodactyly 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 121 of the FBN2 protein (p.Asp121Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs770483769, ExAC 0.005%). This variant has not been reported in the literature in individuals with FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 264204). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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