ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.902G>T (p.Gly301Val) (rs142888621)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617116 SCV000317911 uncertain significance Cardiovascular phenotype 2017-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Center for Medical Genetics Ghent,University of Ghent RCV000407491 SCV000787429 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Color RCV000247580 SCV000904513 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-04 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 5 of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two individuals affected with Marfan syndrome and one individual with thoracic aortic aneurysm (PMID: 26787436, 26188975). To our knowledge, segregation studies have not been reported for this variant. This variant has been identified in 52/277146 chromosomes (45/126652 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
GeneDx RCV000181419 SCV000233721 uncertain significance not specified 2017-01-26 criteria provided, single submitter clinical testing The G301V variant has beenreported as a variant of uncertain significance in a 63 year old male with ascending aortic aneurysmand a family history of aortic disease, though no segregation data was provided (Ziganshin et al.,2015). Additionally, G301V has been identified in several other individuals referred for Marfan/TAADtesting at GeneDx. So far, segregation data is limited or absent for this individual due to lack of clinicalinformation provided. Although the G301V variant was not observed with any significant frequency inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, it has been reported at a low frequency (1/1006 alleles, 0.1%) in individuals ofEuropean background in the 1000 Genomes Project. G301V does not affect a Cysteine residue within acalcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-bindingEGF-like domains represent the majority of pathogenic missense changes associated with Marfansyndrome (Collod-Beroud et al., 2003). Furthermore, the G301V variant is a conservative amino acidsubstitution, which is less likely to impact secondary protein structure as these residues share similarproperties and this substitution occurs at a position where amino acids with similar properties toGlycine are tolerated across species. Nevertheless, in silico analysis is inconsistent in its predictions asto whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000320502 SCV000392642 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000377435 SCV000392643 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000289798 SCV000392644 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000347117 SCV000392645 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000407491 SCV000392646 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000288772 SCV000392647 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000247580 SCV000392648 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000407488 SCV000392649 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000461203 SCV000544950 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 301 of the FBN1 protein (p.Gly301Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs142888621, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with Marfan syndrome, thoracic aortic aneurysm and dissection or vascular anomalies (PMID: 26787436, 26188975, 28655553). ClinVar contains an entry for this variant (Variation ID: 199960). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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