Submissions for variant NM_000138.5(FBN1):c.3455C>T (p.Ala1152Val)

gnomAD frequency: 0.00003  dbSNP: rs539103389

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657904	SCV000779669	uncertain significance	not provided	2018-06-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN1 gene. The A1152V variant has been reported in a patient who met Ghent criteria (Hung et al., 2009) and in one patient with abdominal aortic aneurysm (van de Luijtgaarden et al., 2015). However, this variant is observed in 8/277224 (0.003%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The A1152V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, while the A1152V variant is located within a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780232	SCV000917339	uncertain significance	not specified	2018-02-12	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3455C>T (p.Ala1152Val) results in a non-conservative amino acid change located in the EGF-like domain and EGF-like calcium-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.3455C>T, was observed with an allele frequency of 2.9e-5 in 277224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (2.9e-05 vs 1.10E-04), allowing no conclusion about variant significance. The variant, c.3455C>T, has been reported in an affected individual that fulfilled the Ghent criteria (Hung_2009). However, another publication observed the variant in a patient presenting with aortic dilation and craniofacial and musculoskeletal features, but indicated that due to family segregation (suggesting a lack of cosegregation with disease; more information not provided) it was classified as "suspected benign" (Wooderchak-Donahue_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001182274	SCV001347670	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1152 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 individuals affected with Marfan syndrome (PMID: 19839986, 33775534), sporadic abdominal aortic aneurysm (PMID: 26017485), non-syndromic aortic dissection (PMID: 28973303), intracranial vertebral-basilar artery dissection (PMID: 30115950), and adolescent idiopathic scoliosis (PMID: 32381728). This variant has also been observed in an individual affected with aortopathy but a family segregation study did not support the pathogenicity of this variant (PMID: 25944730). This variant has been identified in 8/282870 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.
Ambry Genetics	RCV001182274	SCV002617163	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-07-26	criteria provided, single submitter	clinical testing	The p.A1152V variant (also known as c.3455C>T), located in coding exon 27 of the FBN1 gene, results from a C to T substitution at nucleotide position 3455. The alanine at codon 1152 is replaced by valine, an amino acid with similar properties, and is located in the cbEGF-like #13 domain. This alteration has been reported in one individual with a clinical diagnosis of Marfan syndrome, meeting Ghent criteria (Hung CC et al. Ann Hum Genet, 2009 Nov;73:559-67). Additionally, this alteration was noted in several isolated thoracic aortic aneurysm cohorts, an idiopathic scoliosis cohort, and an intracranial vertebral-basilar artery dissection cohort (van de Luijtgaarden KM et al. Hum Genet, 2015 Aug;134:881-93; Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57; Tan L et al. Hum Mol Genet, 2017 12;26:4814-4822; Li Z et al. Sci China Life Sci, 2018 12;61:1545-1553; Wang K et al. J Hum Genet, 2018 Nov;63:1119-1128; Jiang H et al. J Med Genet, 2020 06;57:405-413). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002534261	SCV003496795	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1152 of the FBN1 protein (p.Ala1152Val). This variant is present in population databases (rs539103389, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 19839986, 26017485, 28973303, 30115950, 32381728). ClinVar contains an entry for this variant (Variation ID: 546101). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004004185	SCV004814803	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1152 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 individuals affected with Marfan syndrome (PMID: 19839986, 33775534), sporadic abdominal aortic aneurysm (PMID: 26017485), non-syndromic aortic dissection (PMID: 28973303), intracranial vertebral-basilar artery dissection (PMID: 30115950), and adolescent idiopathic scoliosis (PMID: 32381728). This variant has also been observed in an individual affected with aortopathy but a family segregation study did not support the pathogenicity of this variant (PMID: 25944730). This variant has been identified in 8/282870 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.