Submissions for variant NM_000138.5(FBN1):c.4057G>A (p.Gly1353Arg)

gnomAD frequency: 0.00001  dbSNP: rs187177496

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001179399	SCV000742593	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-19	criteria provided, single submitter	clinical testing	The p.G1353R variant (also known as c.4057G>A), located in coding exon 32 of the FBN1 gene, results from a G to A substitution at nucleotide position 4057. The glycine at codon 1353 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an individual reported to have probable Marfan syndrome who did not meet Ghent criteria at the time of study, and who had another FBN1 variant detected (Stheneur C et al. Eur. J. Hum. Genet. 2009 Sep;17:1121-8). This variant has also been detected in an autism cohort (Iossifov I et al. Nature, 2014 Nov;515:216-21). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781366	SCV000919343	uncertain significance	not specified	2017-11-09	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.4057G>A (p.Gly1353Arg) variant involves the alteration of a conserved nucleotide that lies within one of the EGF-like calcium-binding domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/246104 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant has been reported in a patient with probable MFS, though Ghent criteria was not fulfilled, cosegregation data was not provided, and a co-occurring variant that changes a cysteine codon was present in the patient (c.2215T>C/p.Cys739Arg; internally classified as VUS-possibly pathogenic). Taken together, this variant is classified as VUS until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001179399	SCV001344054	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1353 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 cis with p.Cys793Arg variant in an individual affected with Marfan syndrome (PMID: 19293843) and in an individual affected with thoracic aortic dissection (PMID: 31211624). This variant has been identified in 2/251352 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.
Fulgent Genetics, Fulgent Genetics	RCV002483751	SCV002792227	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	2021-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV002532845	SCV003517572	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly1353 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 521833). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 19293843, 31211624; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1353 of the FBN1 protein (p.Gly1353Arg).
Baylor Genetics	RCV003147524	SCV003835491	uncertain significance	Marfan syndrome	2022-08-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003147524	SCV004814762	uncertain significance	Marfan syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1353 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 cis with p.Cys793Arg variant in an individual affected with Marfan syndrome (PMID: 19293843) and in an individual affected with thoracic aortic dissection (Wolford and Hornsby, et al., 2018). This variant has been identified in 2/251352 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.