Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494669 | SCV000582468 | pathogenic | not provided | 2015-09-22 | criteria provided, single submitter | clinical testing | The Y1700C variant in the FBN1 gene has been reported previously in two related individuals with acromicric dysplasia (Le Goff et al., 2011). The Y1700C substitution was not observed 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 Y1700C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (C1706Y, Y1699C/D, Y1696C) have been reported in the Human Gene Mutation Database in association with acromicric and geleophysic dysplasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y1700C as a pathogenic variant. |
| Institute of Human Genetics Munich, |
RCV000022550 | SCV000680229 | pathogenic | Acromicric dysplasia | 2017-12-09 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics and Genomics, |
RCV000494669 | SCV001449824 | pathogenic | not provided | 2016-04-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001851997 | SCV002312213 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2021-09-03 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. Experimental studies have shown that this missense change affects FBN1 function (PMID: 25979247). ClinVar contains an entry for this variant (Variation ID: 29701). This missense change has been observed in individual(s) with acromicric dysplasia (PMID: 21683322, 24339047). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 1700 of the FBN1 protein (p.Tyr1700Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. |
| Clinical Genetics Laboratory, |
RCV000494669 | SCV005197877 | pathogenic | not provided | 2024-03-26 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000022550 | SCV000043839 | pathogenic | Acromicric dysplasia | 2018-01-04 | no assertion criteria provided | literature only |