15-48487395-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000138.5(FBN1):c.3380G>A(p.Gly1127Asp) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1127S) 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3380G>A | p.Gly1127Asp | missense_variant | 28/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3380G>A | p.Gly1127Asp | missense_variant | 27/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3380G>A | p.Gly1127Asp | missense_variant | 28/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 25, 2016 | Variant summary: The FBN1 variant c.3380G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Asp at codon 1127. 4/4 in-silico tools predict this variant to be damaging. The glycine in this position is highly conserved in EGF-like domains of FBN1. Francke et al. (1995) and Khau Van Kien et al. (2010) suggested that mutations such as this may disrupt EGF-like domain folding less dramatically than do substitutions of cysteine or other amino acids important for calcium-binding that cause classic Marfan syndrome, potentially leading to a less severe fibrillinopathy phenotype. Another missense variant in the same codon, p.Gly1127Ser, has been reported to co-segregate in a fibrillinopathy disease family and functional studies show a defect in extracellular matrix deposition (p.Gly1127Ser classified as VUS-possibly pathogenic by LCA). Additionally, p.Gly1127Val, has been reported in one MFS patient in a database (UMD). However, the variant of interest, Gly1127Asp, has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Also, this variant was not found in approximately 121392 control chromosomes from broad and large populations of ExAC. Because of the absence of clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly1127 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762551, 9525872, 12651868). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 495589). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 1127 of the FBN1 protein (p.Gly1127Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at