ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.68C>G (p.Ala23Gly) (rs199560824)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199444 SCV000250091 uncertain significance not specified 2017-07-02 criteria provided, single submitter clinical testing The A23G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A23G variant was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, the A23G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the A23G variant 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 CCA (Collod-Beroud et al., 2003; Frédéric et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000242209 SCV000319421 uncertain significance Cardiovascular phenotype 2015-01-27 criteria provided, single submitter clinical testing The p.A23G variant (also known as c.68C>G), located in coding exon 1 of the FBN2 gene in the signal peptide domain, results from a C to G substitution at nucleotide position 68. The alanine at codon 23 is replaced by glycine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs199560824, but there is no frequency data. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.02% (3/12,862), having been observed in0.04% (3/8,526) of European American alleles and none of 4,336 African American alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhenbutdeleterious bySIFT in silico analyses.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000294775 SCV000452661 likely benign Congenital contractural arachnodactyly 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000294775 SCV000630250 likely benign Congenital contractural arachnodactyly 2020-09-30 criteria provided, single submitter clinical testing

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