Submissions for variant NM_000138.5(FBN1):c.8149G>A (p.Glu2717Lys)

gnomAD frequency: 0.00005  dbSNP: rs187553035

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229179	SCV000283654	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000362980	SCV000392092	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	RCV000270822	SCV000392093	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.
Illumina Laboratory Services, Illumina	RCV000365739	SCV000392095	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	RCV000273444	SCV000392096	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	RCV000330801	SCV000392097	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	RCV000387643	SCV000392098	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	RCV000295866	SCV000392099	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506463	SCV000603627	likely benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506463	SCV000695619	likely benign	not specified	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.8149G>A (p.Glu2717Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 246246 control chromosomes. The observed variant frequency is slightly more than 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.8149G>A has been reported in the literature in individuals affected with ascending aortic aneurysm or single suture craniosynostosis (Ziganshin_2015, Clarke_2018). These report(s) 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000365739	SCV000904472	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2717 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 been reported in one individual affected with ascending aortic aneurysm (PMID: 26188975) and in another individual affected with movement disorders (PMID: 35531120). This variant has been identified in 34/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000387643	SCV000987361	uncertain significance	Marfan syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV001706243	SCV001831860	uncertain significance	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Identified in patients with variable features of a connective tissue disorder in the published literature, including ascending aortic aneurysm (Ziganshin et al., 2015), metopic craniosynostosis (Clarke et al., 2018), and Marfan syndrome (Pinard et al., 2016; Gezdirici et al., 2021); of note, one individual with features of Marfan syndrome was also heterozygous for a pathogenic FBN1 variant, p.(C1138R) (Pinard et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 29168297, 32123317, 33483584, 35531120, 12938084, 27647783, 26188975)
Mayo Clinic Laboratories, Mayo Clinic	RCV001706243	SCV002541276	uncertain significance	not provided	2022-01-03	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000387643	SCV000787399	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing