ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1027G>A (p.Gly343Arg) (rs146726731)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588674 SCV000233723 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing The G343R variant of uncertain significance in the FBN1 gene has been reported previously in a cohort of patients with suspected Marfan syndrome (Tjeldhorn et al., 2006). This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The G343R 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. Additionally, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with FBN1-related. Moreover, the G343R variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1/FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent themajority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000393539 SCV000392626 likely benign Stiff skin syndrome 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000284823 SCV000392627 likely benign Acromicric dysplasia 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000148500 SCV000392628 likely benign Marfan syndrome 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000393542 SCV000392629 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000307377 SCV000392630 likely benign Geleophysic dysplasia 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000364336 SCV000392631 likely benign Weill-Marchesani syndrome 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000315057 SCV000392633 likely benign Ectopia lentis, isolated, autosomal dominant 2018-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000463596 SCV000544839 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 343 of the FBN1 protein (p.Gly343Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs146726731, ExAC 0.04%). This variant has been reported in the literature in individuals suspected of being affected with Marfan syndrome (PMID: 17253931, 24311428, 17663468). Additionally, this variant has been reported in an individual affected with familial cervical artery dissection (PMID: 31008308). ClinVar contains an entry for this variant (Variation ID: 161244). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181421 SCV000603613 uncertain significance not specified 2016-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588674 SCV000695447 likely benign not provided 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.1027G>A (p.Gly343Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense change in a TB domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in ExAC and control cohorts from the literature at a frequency of 0.0001565 (19/121412 control chromosomes), which is slightly above (~1.5 times) the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this variant may be a benign polymorphism. While several studies identified the variant in patients without strong evidence for causality, one family study found the variant co-occurring with a reportedly pathogenic COL3A1 variant (p.G324S), and another affected family member did not carry the variant of interest (Grond-Ginsbach_2017), further supporting a benign impact for the variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant with conflicting interpretations, including uncertain significance and likely benign. Taken together, this variant is classified as likely benign.
Ambry Genetics RCV000617536 SCV000738749 uncertain significance Cardiovascular phenotype 2019-02-27 criteria provided, single submitter clinical testing The p.G343R variant (also known as c.1027G>A), located in coding exon 9 of the FBN1 gene, results from a G to A substitution at nucleotide position 1027. The glycine at codon 343 is replaced by arginine, an amino acid with dissimilar properties. This alteration was first reported in a cohort of 105 patients with suspected Marfan syndrome (MFS) (Tjeldhorn L et al. Genet. Test., 2006;10:258-64). Later, the same group reported that the individual carrying this alteration was diagnosed with MFS (Rand-Hendriksen S et al. Am. J. Med. Genet. A. 2007;143A:1968-77), and had increased FBN1 mRNA in fibroblasts (Tjeldhorn L et al. BMC Med. Genet. 2015;16:113). This alteration was also described in a patient with spontaneous pneumothorax and Marfanoid habitus, and was detected in two relatives reported to have MFS in another study (Viveiro C et al. BMJ Case Rep, 2013;2013; Becerra-Muñoz VM. Orphanet J Rare Dis. 2018;13(1):16). This variant co-occurred with an alteration in COL3A1 in a family with carotid artery dissection, where the current variant was absent in one affected relative (Grond-Ginsbach C et al. European Stroke J. 2017; 2(2):137–143). In addition, this variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659507 SCV000781327 uncertain significance Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000393542 SCV000904495 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 343 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals suspected of having Marfan syndrome (PMID: 17253931, 17663468, 24311428). This variant has been identified in 52/282706 chromosomes in the general population and by the Genome Aggregation Database (gnomAD). Although the relatively high allele frequency in the population suggests that this variant is unlikely disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588674 SCV001149463 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148500 SCV000190209 uncertain significance Marfan syndrome 2014-06-01 no assertion criteria provided research

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