rs201361628
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP6BS2
The NM_000138.5(FBN1):c.6577G>A(p.Glu2193Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: 4.98
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
In a domain EGF-like 37; calcium-binding (size 39) in uniprot entity FBN1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000138.5
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
BP6
Variant 15-48434633-C-T is Benign according to our data. Variant chr15-48434633-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=13}. Variant chr15-48434633-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.6577G>A | p.Glu2193Lys | missense_variant | 54/66 | ENST00000316623.10 | NP_000129.3 | |
FBN1 | NM_001406716.1 | c.6577G>A | p.Glu2193Lys | missense_variant | 53/65 | NP_001393645.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.6577G>A | p.Glu2193Lys | missense_variant | 54/66 | 1 | NM_000138.5 | ENSP00000325527 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251226Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135774
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461522Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727092
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:14Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | The p.E2193K variant (also known as c.6577G>A), located in coding exon 53 of the FBN1 gene, results from a G to A substitution at nucleotide position 6577. The glutamic acid at codon 2193 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as homozygous in an individual with features of Marfan syndrome, including aortic dilatation and ectopia lentis, but clinical details were limited and additional family members were not evaluated (Arnaud P et al. J. Med. Genet., 2017 Feb;54:100-103). This alteration was also detected in one individual from a vascular anomalies cohort, but clinical details were not provided (Mattassi R et al. J Vasc Surg. 2018 03;67(3):922-932.e11). 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 alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | This missense variant replaces glutamic acid with lysine at codon 2193 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with Marfan syndrome (PMID: 12938084, 27582083, Magyar 2011, dissertation, University of Zurich), in an individual with vascular anomalies (PMID: 28655553), and in a family with Parkinson's disease (Dheeraj, 2018). This variant has also been identified in 8/282630 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 08, 2018 | - - |
Marfan syndrome Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces glutamic acid with lysine at codon 2193 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with Marfan syndrome (PMID: 12938084, 27582083, Magyar 2011, dissertation, University of Zurich), in an individual with vascular anomalies (PMID: 28655553), and in a family with Parkinson's disease (Dheeraj, 2018). This variant has also been identified in 8/282630 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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 (ClinVar Variant ID# 255306; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28655553, 27582083) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | FBN1: PS4:Moderate, PM2:Supporting - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2018 | The FBN1 c.6577G>A; p.Glu2193Lys variant (rs201361628), is reported in the literature in the homozygous state in at least one individual affected with Marfan syndrome (Arnaud 2017), and in the heterozygous state in individuals with vascular anomalies (Mattassi 2018). This variant is reported as uncertain significance/likely benign by multiple laboratories in ClinVar (Variation ID: 255306), and is found in the general population with an overall allele frequency of 0.002% (6/276,956 alleles) in the Genome Aggregation Database. The glutamic acid at codon 2193 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Glu2193Lys variant is uncertain at this time. References: Arnaud P et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet. 2017 Feb;54(2):100-103. Mattassi R et al. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg. 2018 Mar;67(3):922-932.e11. - |
Stiff skin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Weill-Marchesani syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Acromicric dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Ectopia lentis 1, isolated, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Vest4
MVP
MPC
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at