Submissions for variant NM_000138.5(FBN1):c.3509G>A (p.Arg1170His)

gnomAD frequency: 0.00168  dbSNP: rs137854475

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000148494	SCV003762198	benign	Marfan syndrome	2023-02-01	reviewed by expert panel	curation	The NM_00138 c.3509G>A, is a missense variant in FBN1 predicted to cause a substitution of an arginine acid by histidine at amino acid 1170 (p.Arg1170His). This variant has been previously reported in several apparently unrelated individuals with Marfan syndrome (PMID 26787436, internal data), incomplete Marfan syndrome, including with skeletal features and/or mitral valve prolapse (PMID 7870075, 9837823, 17418587, 17627385, 17657824), in individuals with isolated thoracic aortic aneurysm and/or dissection (internal data) and in other phenotypes like arterial dissection and venous bleeding (internal data). This variant was found to segregate with disease in seven affected individuals with incomplete Marfan syndrome from three families (PMID 7870075, 9837823, internal data). This variant has been found to co-occur with different pathogenic variants in FBN1 (BP2), TGFBR1, and TGFRB2 (BP5) (internal data). This variant has been identified in 286 individuals of European non-Finnish origin (MAF: 0.2%) (BA1; https://gnomad.broadinstitute.org/, version 2.1.1). The variant in FBN1 has been reported 21 times in ClinVar: 16 times as likely benign and 5 times as uncertain significance (Variation ID: 16451). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.502). Functional studies, including in-vitro splicing analysis, found that this variant had no impact on splicing (PMID 21895641, 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments, PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1, BP2, BP5.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154459	SCV000204128	likely benign	not specified	2015-03-24	criteria provided, single submitter	clinical testing	p.Arg1170His in exon 28 of FBN1: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (124/66684) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs137854475). Arginine (Arg) at position 1170 is not conserved in evolut ionarily distant species and at least 10 birds, reptiles, and fish carry a histi dine (His) at this position, supporting that this change may be tolerated. This variant has been identified by our laboratory in 6 individuals with features of Marfan syndrome; however, two of these individuals were compound heterozygotes f or a pathogenic variant sufficient to explain their disease. Although this varia nt has been reported in individuals with features of Marfan syndrome in the lite rature, this variant is likely benign based on its frequency in the general popu lation, lack of conservation, and the presence of other variants to explain dise ase in multiple individuals.
Eurofins Ntd Llc (ga)	RCV000589339	SCV000228689	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000154459	SCV000233791	likely benign	not specified	2017-12-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000148494	SCV000257635	uncertain significance	Marfan syndrome	2015-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV001084627	SCV000283623	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242225	SCV000317678	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-04-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV000148494	SCV000328720	uncertain significance	Marfan syndrome	2017-12-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000290413	SCV000392418	likely benign	Geleophysic dysplasia	2017-04-27	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 Laboratory Services, Illumina	RCV000340663	SCV000392419	likely benign	Ectopia lentis 1, isolated, autosomal dominant	2017-04-27	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 Laboratory Services, Illumina	RCV000242225	SCV000392420	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-04-27	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 Laboratory Services, Illumina	RCV000305937	SCV000392421	likely benign	Stiff skin syndrome	2017-04-27	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 Laboratory Services, Illumina	RCV000148494	SCV000392423	likely benign	Marfan syndrome	2017-04-27	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 Laboratory Services, Illumina	RCV000297783	SCV000392424	likely benign	Weill-Marchesani syndrome	2017-04-27	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 Laboratory Services, Illumina	RCV000357267	SCV000392425	likely benign	Acromicric dysplasia	2017-04-27	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000154459	SCV000603629	likely benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154459	SCV000695516	likely benign	not specified	2021-07-27	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3509G>A (p.Arg1170His) results in a non-conservative amino acid change located in one of the EGF-like calcium-binding domains (IPR001881) 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 0.0014 in 396164 control chromosomes in the gnomAD database (version 2.1 and 3.1 datasets), including 1 homozygote. The observed variant frequency is approximately 12-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 benign. c.3509G>A has been reported in the literature in cohorts of individuals affected with Marfan Syndrome or Marfan-like syndrome (e.g. Hayward_1994, Montgomery_1998, Comeglio_2007, Robinson_2011, Howarth_2007, Waldmuller_2007, Volk_2014, Franken_2016), however, in some of these studies an incomplete Marfan phenotype was noted, or no exact phenotype information was provided. In a recent case-control study the variant was found in 11 cases of imaging supported nonsyndromic aortopathy and/or mitral valve disease, and in 14 carriers without cardiovascular disease, whereas only 12/101 (12%) of controls without pathogenic FBN1 variants (with sufficient imaging), had evidence of mitral valve or aortic disease in this study (Damrauer_2019). Co-occurrences with other pathogenic variants have been reported (FBN1 c.4913delA, p.Tyr1638fsX2 and FBN1 c.1633C>T, p.Arg545Cys, in internal LCA samples), providing supporting evidence for a benign role. Two publications reported that the variant had no effect on splicing examining blood RNA samples (Robinson_2011, Wai_2020), however these data do not allow any conclusion for the protein level effect of the variant. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 mostly without evidence for independent evaluation, and classified the variant as VUS (n=5), or likely benign (n=10). Based on the evidence outlined above, though the variant could be associated with an increased risk for nonsyndromic aortopathy and/or mitral valve disease, it was classified for the Marfan Syndrome phenotype as likely benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767968	SCV000898695	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	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 29 p.Arg1170His (c.3509G>A): This variant has been reported in at least four individuals with incomplete/suspected Marfan syndrome, segregating with suspected features in at least two different families (Hayward 1994 PMID:7870075, Montgomery 1998 PMID:9837823, Comeglio 2007 PMID:17657824, Stavropoulos 2016 PMID:28567303). Of note, these reported probands presented with primarily skeletal abnormalities; none fully met Ghent criteria for Marfan syndrome. Additionally, this variant did not segregate with disease in one family with suspected Marfan syndrome that was tested in our lab. This variant is present in 0.2% (286/129170) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-48779352-C-T) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:16451). This variant amino acid Histidine (His) is present in several bird species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000242225	SCV000911141	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-16	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000154459	SCV000923434	uncertain significance	not specified	2019-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000148494	SCV001139610	likely benign	Marfan syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000242225	SCV001333386	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589339	SCV004129813	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FBN1: BS1
PreventionGenetics, part of Exact Sciences	RCV004532380	SCV004739472	likely benign	FBN1-related disorder	2020-03-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000148494	SCV004814796	likely benign	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000360569	SCV000038193	pathogenic	MASS syndrome	1998-12-01	flagged submission	literature only
CSER _CC_NCGL, University of Washington	RCV000148494	SCV000190201	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
Blueprint Genetics	RCV001837435	SCV000206952	uncertain significance	Disproportionate tall stature	2014-03-25	no assertion criteria provided	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000148494	SCV000786972	likely benign	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000845006	SCV000986836	not provided	Marfan syndrome; MASS syndrome; Congenital aneurysm of ascending aorta; Weill-Marchesani syndrome; Ectopia lentis		no assertion provided	phenotyping only	Variant interpretted as Likely benign and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomics England Pilot Project, Genomics England	RCV000148494	SCV001760349	likely pathogenic	Marfan syndrome		flagged submission	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589339	SCV001807117	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589339	SCV001932183	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589339	SCV001967693	likely benign	not provided		no assertion criteria provided	clinical testing