Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001039138 | SCV001202651 | uncertain significance | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-07-16 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2215 of the FBN1 protein (p.Leu2215Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 837738). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Color Diagnostics, |
RCV001178703 | SCV001343215 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-02-28 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with methionine at codon 2215 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 1/250978 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002481869 | SCV002783198 | uncertain significance | 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 | 2021-08-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235450 | SCV003934301 | uncertain significance | not specified | 2023-05-22 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.6643C>A (p.Leu2215Met) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250978 control chromosomes (gnomAD) . The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6643C>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |