Submissions for variant NM_000138.5(FBN1):c.1027G>A (p.Gly343Arg)

gnomAD frequency: 0.00021  dbSNP: rs146726731

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588674	SCV000233723	uncertain significance	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Published in association with confirmed or suspected Marfan syndrome as well as carotid artery dissection or thoracic aortic aneurysm; however, one individual was found to harbor another variant that likely contributed to the phenotype, and an affected relative of a different proband was reported to be absent for this variant (PMID: 17253931, 17663468, 24311428, 26684006, 31008308, 29357934, 36889877); Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 27647783, 24311428, 24941995, 26332594, 25812041, 26684006, 28254189, 29357934, 30122538, 17663468, 31008308, 17253931, 33910934, 31322791, 35886052, 36889877, 12938084)
Illumina Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV000315057	SCV000392633	likely benign	Ectopia lentis 1, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463596	SCV000544839	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-12-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588674	SCV000603613	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	The FBN1 c.1027G>A; p.Gly343Arg variant (rs146726731; ClinVar Variation ID: 161244) has been reported in multiple cohorts of individuals with suspected or confirmed Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007, Viveiro 2013, Becerra-Munoz 2018, Fernandez-Alvarez 2022), including a purported de novo observation (Fernandez-Alvarez 2022). However, this variant was identified alongside other pathogenic variation in other genes in affected patients (Grond-Ginsbach 2017 and Arbustini 2017), and failed to co-segregate with disease in two cousins affected with cervical artery dissection (Grond-Ginsbach 2017). Additionally, this variant is also found in the non-Finnish European population with an allele frequency of 0.03% (33/129,054 alleles) in the Genome Aggregation Database (v2.1.1) and reported in several additional studies of variant in the general population (Amendola 2015, Groth 2016, Olfson 2015, Yang 2014). This variant is located in the TGF-beta binding (TB) domain of FBN1 (not in an EGF domain), though computational analyses predict that this variant is deleterious (REVEL: 0.863). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Amendola et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015; 25(3): 305-315. PMID: 25637381 Arbustini E et al. Reply: A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation. J Am Coll Cardiol. 2017 Mar 7;69(9):1210-1211. PMID: 28254189. Becerra-Munoz VM et al The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J Rare Dis. 2018 Jan 22;13(1):16. PMID: 29357934 Fernandez-Alvarez P et al. A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome. J Med Genet. 2022 Jun;59(6):605-612. PMID: 33910934. Grond-Ginsbach C et al. Next generation sequencing analysis of patients with familial cervical artery dissection. Eur Stroke J. 2017 Jun;2(2):137-143. PMID: 31008308 Groth et al. Difficulties in diagnosing Marfan syndrome using current FBN1 databases. Genet Med. 2016; 18(1): 98-102. PMID: 25812041 Olfson et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One. 2015; 10(9): e0135193. PMID: 26332594 Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 Sep 1;143A(17):1968-77. PMID: 17663468. Tjeldhorn et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006; 10(4): 258-264. PMID: 17253931 Viveiro et al. Spontaneous pneumothorax as manifestation of Marfan syndrome. BMJ Case Rep. 2013; 2013. PMID: 24311428 Yang et al. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome. BMC Genet. 2014; 15:74. PMID: 24941995
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181421	SCV000695447	likely benign	not specified	2024-08-06	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1027G>A (p.Gly343Arg) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251406 control chromosomes, predominantly at a frequency of 0.00043 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011). c.1027G>A has been reported in the literature in individuals affected with Aortopathy or MFS without strong evidence for causality (Tjeldhorn_2006, Tjeldhorn_2015, Rand-Hendriksen_2007, Viveiro_2013, Grond-Ginsbach_2017, Becerra-Munoz_2018, Kasak_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. Co-occurrences with other pathogenic variant(s) have been reported ( COL3A1 c.970G>A, p.G324S), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17253931, 17663468, 24941995, 26332594, 25637381, 25812041, 24311428, 29357934, 31008308, 31322791, 26684006). ClinVar contains an entry for this variant (Variation ID: 161244). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000393542	SCV000738749	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-11-06	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. Eur Stroke J, 2017 Jun;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 disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000393542	SCV000904495	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-20	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 reported 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 reported in an individual affected with cervical artery dissection (PMID: 31008308); this individual also carried a pathogenic variant in the COL3A1 gene. This variant has been identified in 52/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000588674	SCV001149463	uncertain significance	not provided	2020-11-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148500	SCV004823090	uncertain significance	Marfan syndrome	2024-02-05	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 reported 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 reported in an individual affected with cervical artery dissection (PMID: 31008308); this individual also carried a pathogenic variant in the COL3A1 gene. This variant has been identified in 52/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington	RCV000148500	SCV000190209	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588674	SCV001929590	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588674	SCV001952569	uncertain significance	not provided		no assertion criteria provided	clinical testing