rs886038869
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.8006G>T(p.Gly2669Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2669C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.8006G>T | p.Gly2669Val | missense_variant | 64/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.8006G>T | p.Gly2669Val | missense_variant | 63/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.8006G>T | p.Gly2669Val | missense_variant | 64/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2018 | The p.G2669V variant (also known as c.8006G>T), located in coding exon 63 of the FBN1 gene, results from a G to T substitution at nucleotide position 8006. The glycine at codon 2669 is replaced by valine, an amino acid with dissimilar properties. This alteration is located in the cbEGF-like #43 domain, and was reported as occurring de novo in a case with classical Marfan syndrome (MFS) (Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-1128). Another alteration affecting this amino acid (p.G2669C) has been reported in a case of suspected MFS (Baudhuin LM et al. J Hum Genet. 2015;60:241-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2016 | The G2669V likely pathogenic variant in the FBN1 gene has been reported previously as occurring de novo in one individual with classic Marfan syndrome (Stheneur et al., 2009). The G2669V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the G2669V variant is a conservative amino acid substitution, it occurs at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense variants in nearby residues (T2661C, C2663S, G2668C, G2668D, ) have been reported in the Human Gene Mutation Database in association with FBN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Although the G2669V variant is located within a calcium-binding EGF-like domain of the FBN1 gene, it does not affects a Cysteine residue. 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).Therefore, this variant is likely pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly2669 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29543232), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 263642). This missense change has been observed in individual(s) with FBN1-related disease (PMID: 19293843; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2669 of the FBN1 protein (p.Gly2669Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at