ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.6910G>A (p.Asp2304Asn) (rs368802769)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200348 SCV000250235 uncertain significance not provided 2018-10-05 criteria provided, single submitter clinical testing p.Asp2304Asn (GAC>AAC): c.6910 G>A in exon 55 of the FBN2 gene (NM_001999.3) The D2304N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D2304N variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D2304N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1,TAAD
Illumina Clinical Services Laboratory,Illumina RCV000342918 SCV000452559 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000342918 SCV000630251 benign Congenital contractural arachnodactyly 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619256 SCV000738976 uncertain significance Cardiovascular phenotype 2016-07-08 criteria provided, single submitter clinical testing The p.D2304N variant (also known as c.6910G>A), located in coding exon 55 of the FBN2 gene, results from a G to A substitution at nucleotide position 6910. The aspartic acid at codon 2304 is replaced by asparagine, an amino acid with highly similar properties, and is located in the cb EGF-like #36 domain. This variant was previously reported in the SNPDatabase as rs368802769. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (8/106070). The highest observed frequency was 0.02% (4/16492) of South Asian alleles, including one homozygote. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles. This amino acid position is well conserved in available vertebrate species; however, asparagine 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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