rs776667707
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP6BS2
The NM_000138.5(FBN1):c.3503A>G(p.Asn1168Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,614,074 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1168I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3503A>G | p.Asn1168Ser | missense_variant | 29/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3503A>G | p.Asn1168Ser | missense_variant | 28/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3503A>G | p.Asn1168Ser | missense_variant | 29/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251440Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135896
GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461886Hom.: 1 Cov.: 31 AF XY: 0.000100 AC XY: 73AN XY: 727248
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74344
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 27, 2023 | 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2020 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 13, 2019 | 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. - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2021 | 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 expected for a pathogenic variant in FBN1 causing Marfan Syndrome (7.2e-05 vs 0.00011), allowing no conclusion about variant significance. c.3503A>G has been reported in the literature in patients with suspected MFS, 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2022 | 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. - |
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | 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. - |
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 01, 2020 | - - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 09, 2021 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at