Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002315948 | SCV000739797 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2021-04-05 | criteria provided, single submitter | clinical testing | The c.2673A>G pathogenic mutation (also known as p.Q891Q) located in coding exon 21, results from an A to G substitution at nucleotide position 2673 of the FBN1 gene. This nucleotide substitution does not change the amino acid at codon 891. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FBN1-related disease (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have revealed that the predicted alternate donor splice site four base pairs upstream of the native donor splice site is utilized, resulting in a frameshift with a premature stop codon that is subject to nonsense-mediated mRNA decay (Center for Human Genetics, Cleveland, OH, pers. comm.). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Blueprint Genetics | RCV000788969 | SCV000928275 | likely pathogenic | not provided | 2019-03-15 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001062663 | SCV001227478 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2019-09-24 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This variant has been observed to be de novo in an individual with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 520242). This sequence change affects codon 891 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. |
| Gene |
RCV000788969 | SCV001794493 | likely pathogenic | not provided | 2019-06-04 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 520242; Landrum et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may create a new splice donor site four nucleotide positions upstream of the native donor site; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown |