Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002314188 | SCV000738455 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-08-12 | criteria provided, single submitter | clinical testing | The p.G1042S variant (also known as c.3124G>A), located in coding exon 25 of the FBN1 gene, results from a G to A substitution at nucleotide position 3124. The glycine at codon 1042 is replaced by serine, an amino acid with similar properties, and is located in the cb EGF-like #11 domain. This alteration was detected in a 30 year old female reported to have Marfan syndrome who had ectopia lentis, pectus carinatum, and pes planus (Attanasio M et al. Clin Genet. 2008;74:39-46). Another alteration affecting this amino acid (p.G1042D, c.3125G>A) was reported in a 2 year old patient who met major cardiovascular and skeletal criteria but who did not fulfill Ghent criteria at the time of study (Sakai H et al. Am J Med Genet A. 2006;140:1719-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| 3billion, |
RCV002250670 | SCV002521632 | likely pathogenic | Marfan syndrome | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic (Clinvar ID: VCV000519571). A different missense change at the same codon (p.Gly1042Asp) has been reported to be associated with FBN1 related disorder (ClinVar ID: VCV000519740 / PMID: 16835936). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Fulgent Genetics, |
RCV002483725 | SCV002789285 | likely pathogenic | Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002531809 | SCV003442944 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-05-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1042 of the FBN1 protein (p.Gly1042Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBN1-related conditions (PMID: 18435798; Invitae). ClinVar contains an entry for this variant (Variation ID: 519571). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1042 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 16835936), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |