ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5183C>T (p.Ala1728Val) (rs1131691804)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626616 SCV000747317 pathogenic Metaphyseal chondrodysplasia 2017-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626617 SCV000747318 likely pathogenic Short stature; Wide mouth; Wide nasal bridge; Relative macrocephaly 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000493791 SCV000582880 likely pathogenic not provided 2016-05-05 criteria provided, single submitter clinical testing The A1728V was reported once as a de novo variant in an individual with clinical symptoms of geleophysic dysplasia (Le Goff et al., 2011). The A1728V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense pathogenic variant at the same residue (A1728T) and in nearby residues (G1726V, S1722C, N1730I, C1733Y) have been reported in the Human Gene Mutation Database in association with geleophysic/acromicric dysplasia (Stenson et al., 2014; Cain et al., 2012). Nevertheless, the A1728V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no functional studies for the A1728V variant have been performed, to our knowledge.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV000779168 SCV000915687 likely pathogenic Geleophysic dysplasia 2017-04-27 criteria provided, single submitter clinical testing The FBN1 c.5183C>T (p.Ala1728Val) missense variant has been reported in two studies and found in a total of four individuals from three unrelated families affected with FBN1-related disorders, including acromicric dysplasia and geleophysic dysplasia, all in a heterozygous state (Le Goff et al. 2011; de Bruin et al. 2016). The individual reported in Le Goff et al. (2011) study was de novo for the variant, while one patient reported in de Bruin et al. (2016) study inherited the variant from affected mother. The variant was absent from the 1000 Genomes Project, Exome Sequencing Project, the Exome Aggregation Consortium and the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.Ala1728Val is classified as likely pathogenic for FBN1-related disorders. This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population.

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