ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.5966G>A (p.Arg1989His)

gnomAD frequency: 0.00003  dbSNP: rs189964478
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197720 SCV000250119 uncertain significance not provided 2021-08-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213240; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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 FBN2 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 FBN2-related disorders (Frederic et al., 2009); This variant is associated with the following publications: (PMID: 26582918)
Labcorp Genetics (formerly Invitae), Labcorp RCV001053741 SCV001218017 benign Congenital contractural arachnodactyly 2024-08-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002354544 SCV002656496 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-03-27 criteria provided, single submitter clinical testing The p.R1989H variant (also known as c.5966G>A), located in coding exon 47 of the FBN2 gene, results from a G to A substitution at nucleotide position 5966. The arginine at codon 1989 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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