ClinVar Miner

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

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000617116 SCV000317911 uncertain significance Cardiovascular phenotype 2017-11-15 criteria provided, single submitter clinical testing The p.G301V variant (also known as c.902G>T), located in coding exon 8 of the FBN1 gene, results from a G to T substitution at nucleotide position 902. The glycine at codon 301 is replaced by valine, an amino acid with dissimilar properties, and is located in the cbEGF-like #02 domain. This alteration has been reported in individuals from thoracic aortic aneurysm and dissection (TAAD), Marfan syndrome, and vascular malformation cohorts; however, clinical details were limited (Ziganshin BA et al. Ann. Thorac. Surg., 2015 Nov;100:1604-11; Franken R et al. Eur. Heart J., 2016 Nov;37:3285-3290; Mattassi R et al. J. Vasc. Surg., 2017 Jun;[Epub ahead of print]). Based on data from gnomAD, the T allele has an overall frequency of approximately 0.019% (52/277146). The highest observed frequency was 0.036% (45/126652) of non-Finnish European alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000377435 SCV000392643 benign Ectopia lentis, isolated, autosomal dominant 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000289798 SCV000392644 benign Acromicric dysplasia 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000347117 SCV000392645 benign Geleophysic dysplasia 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000407491 SCV000392646 likely benign Marfan syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000288772 SCV000392647 benign Stiff skin syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000247580 SCV000392648 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000407488 SCV000392649 likely benign Weill-Marchesani syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000461203 SCV000544950 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-10-30 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.
Color Health, Inc RCV000247580 SCV000904513 likely benign Familial thoracic aortic aneurysm and aortic dissection 2020-04-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000995347 SCV001149465 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000181419 SCV001361427 likely benign not specified 2019-03-31 criteria provided, single submitter clinical testing Variant summary: FBN1 c.902G>T (p.Gly301Val) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 277146 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.902G>T has been reported in the literature in individuals affected with Marfan Syndrome, vascular anomalies and ascending aortic aneurysm (Mattassi_2018, Franken_2016, Ziganshin_2015). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as likely benign (1x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181419 SCV001365724 uncertain significance not specified 2019-01-02 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 2 Marfan probands (PubMed: 26787436). Computational tools predict benign. Identified in 0.04% of European chromosoems in gnomAD.
Mayo Clinic Laboratories, Mayo Clinic RCV000995347 SCV001714519 uncertain significance not provided 2019-09-23 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000407491 SCV000787429 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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