Submissions for variant NM_000138.5(FBN1):c.7852G>A (p.Gly2618Arg)

gnomAD frequency: 0.00019  dbSNP: rs141133182

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035279	SCV000058927	uncertain significance	Marfan syndrome	2021-09-07	criteria provided, single submitter	clinical testing	The p.Gly2618Arg variant in FBN1 has been reported in at least six individuals with clinical features of Marfan syndrome (Loeys 2001 PMID: 11700157, Mátyás 2002 PMID: 11933199, Comeglio 2007 PMID: 17657824, Turner 2009 PMID: 19161152, Campens 2015 PMID: 25644172, LMM data) but has also been reported in apparently healthy individuals in population biobanks and in individuals not meeting diagnostic criteria for Marfan syndrome (Groth 2016 PMID: 25812041, Damrauer 2019 PMID: 31211626). Moreover, it has been identified in 0.05% (15/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data and the variant frequency suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PP3.
CSER _CC_NCGL, University of Washington	RCV000035279	SCV000190203	uncertain significance	Marfan syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of Marfan syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics	RCV001184743	SCV000319310	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-10-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464816	SCV000544845	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-12-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000154182	SCV000603654	uncertain significance	not specified	2017-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154182	SCV000695611	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7852G>A (p.Gly2618Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251212 control chromosomes (gnomAD). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is benign. c.7852G>A has been reported in the literature in at least ten patients who did not fulfill the revised Ghent criteria: all these patients shared common features of incomplete MFS and presented with minor to major skeletal involvement and minimal to no ocular, cardiovascular and skin involvement (Loeys_2001, Howarth_2007, Comeglio_2007, Turner_2009, Baudhuin_2015, Campens_2015, Damrauer_2019). The fact that this variant was found in apparently healthy individuals from ESP and ExAC cohorts does not rule out mild pathogenicity of this variant, since based on the phenotype prevalence of MFS (1/5000), the expected prevalence of MFS in the ESP population was calculated to be 1.3 subjects (Yang_2014). Yang and co-authors attempted to collect clinical and family data for ESP participants carrying this variant, but were not successful. These data do not allow any conclusion about variant significance. At least one co-occurrence with another pathogenic variant has been reported (FBN1 c.6431A>G, p.Asn2144Ser), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 12203992, 11700157, 11933199, 17657824, 17627385, 19161152, 24941995, 25652356, 25637381, 25944730, 25812041, 19780835, 25644172, 26498160, 27647783, 28301460, 31211626). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=9) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
SIB Swiss Institute of Bioinformatics	RCV000035279	SCV000803444	uncertain significance	Marfan syndrome	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Marfan syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:25652356).
Fulgent Genetics, Fulgent Genetics	RCV000765219	SCV000896455	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	2021-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184743	SCV001350799	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2025-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2618 of the FBN1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. This variant has been reported in an individual affected with thoracic aortic dissection (PMID: 25644172), in an individual affected with Marfan syndrome (PMID: 17627385), and in several individuals affected with a Marfan-like phenotype (PMID: 11700157, 17657824, 19161152, 25652356). This variant has also been identified in 55/282620 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000035279	SCV001430638	uncertain significance	Marfan syndrome	2020-06-10	criteria provided, single submitter	clinical testing	This variant has been reported in multiple patients with a suspected or confirmed diagnosis of Marfan syndrome or a related disorder. FBN1 c.7852G>A (rs141133182) is rare (<0.1%) in a large population dataset (gnomAD: 55/282620 total alleles; 0.02%; no homozygotes). This variant has been reported in ClinVar. Three bioinformatic tools queried7,8 predict that this substitution would be damaging, and the glycine residue at this position is highly evolutionarily conserved across all species assessed9. We consider the clinical significance of c.7852G>A to be uncertain at this time.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000035279	SCV002767474	uncertain significance	Marfan syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (55 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF domain. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported many times as a VUS, and observed in at least six individuals with features of Marfan syndrome, and several others with thoracic aortic dissection. However, none fullfilled Ghent criteria (ClinVar, PMID: 31227806, PMID: 27106435). It was also seen in six individuals from a large biobank cohort, where only two had a cardiovascular phenotype (PMID: 31211626). (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001184743	SCV004240596	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-05-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000035279	SCV004816733	uncertain significance	Marfan syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2618 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 an individual affected with thoracic aortic dissection (PMID: 25644172), as well as in several individuals affected with Marfan syndrome (PMID: 17627385) or with a Marfan-like phenotype (PMID: 11700157, 17657824, 19161152, 25652356). This variant has also been identified in 55/282620 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.
Center for Medical Genetics Ghent, University of Ghent	RCV000035279	SCV000787370	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing