Submissions for variant NM_000138.5(FBN1):c.3503A>G (p.Asn1168Ser)

gnomAD frequency: 0.00004  dbSNP: rs776667707

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001180575	SCV000319603	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-11	criteria provided, single submitter	clinical testing	The p.N1168S variant (also known as c.3503A>G), located in coding exon 28 of the FBN1 gene, results from an A to G substitution at nucleotide position 3503. The asparagine at codon 1168 is replaced by serine, an amino acid with highly similar properties and is located in the cb EGF-like #14 domain. This alteration was identified in an individual suspected of having Marfan syndrome (MFS); however, clinical details were not provided (Ogawa N et al. Am J Cardiol. 2011;108(12):1801-7). This variant seen in a proband with some features consistent with MFS, but was also detected in the reportedly unaffected father (Baudhuin LM et al. J Hum Genet, 2015 May;60:241-52). This amino acid position is not well 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 variant remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455893	SCV000539148	likely benign	not specified	2022-06-16	criteria provided, single submitter	clinical testing	The p.Asn1168Ser variant in FBN1 has been classified as likely benign because it has been identified in 0.01% (18/251440) chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, including the presence of this amino acid (Serine; Ser) in rat. ACMG/AMP criteria applied: BS1, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455893	SCV000695515	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3503A>G (p.Asn1168Ser) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome, allowing no conclusion about variant significance. c.3503A>G has been reported in the literature in patients with suspected MFS, and the variant was found in the unaffected father of one of the patients (patient did not meet the Ghent criteria), suggesting that the variant may be benign (example, Baudhuin_2015). Co-segregation data was not provided for some of the patients, and it is unknown if the Ghent criteria were met in all of them (example, Ogawa_2011, Takeda_2018). 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: 21907952, 24941995, 25652356, 26269718, 29848614). ClinVar contains an entry for this variant (Variation ID: 263998). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818595	SCV000959217	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180575	SCV001345534	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1168 of the FBN1 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with Marfan syndrome (PMID: 21907952, 25652356). This variant has been identified in 18/251440 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587326	SCV001471538	uncertain significance	not provided	2019-09-13	criteria provided, single submitter	clinical testing	The FBN1 c.3503A>G; p.Asn1168Ser variant (rs776667707) is reported in the literature in individuals affected with Marfan syndrome, but was also identified in one individual’s unaffected father (Baudhuin 2015, Ogawa 2011). This variant is reported in ClinVar (Variation ID: 263998), and is found in the general population with an overall allele frequency of 0.007% (18/251440 alleles) in the Genome Aggregation Database. The asparagine at codon 1168 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Asn1168Ser variant is uncertain at this time. References: Baudhuin LM et al. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet. 2015 May;60(5):241-52. Ogawa N et al. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011 Dec 15;108(12):1801-7.
GeneDx	RCV000587326	SCV001813578	uncertain significance	not provided	2020-04-03	criteria provided, single submitter	clinical testing	Reported in two unrelated individuals with a suspected diagnosis of Marfan syndrome; one individual inherited the variant from his unaffected father (Ogawa et al., 2011; Baudhuin et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in 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 FBN1-related disorders (Collod-Beroud et al., 2003); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 263998; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25652356, 24941995, 26269718, 21907952)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278238	SCV002566529	uncertain significance	Connective tissue disorder	2020-04-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500949	SCV002789617	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	2021-12-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995705	SCV004814799	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1168 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 performed for this variant. This variant has been reported in two individuals affected with Marfan syndrome (PMID: 21907952, 25652356). This variant has been identified in 18/251440 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.