rs363855
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2
The NM_000138.5(FBN1):c.1087G>A(p.Gly363Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G363G) has been classified as Likely benign.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.1087G>A | p.Gly363Ser | missense_variant | 10/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.1087G>A | p.Gly363Ser | missense_variant | 9/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.1087G>A | p.Gly363Ser | missense_variant | 10/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.1087G>A | p.Gly363Ser | missense_variant, NMD_transcript_variant | 10/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.1087G>A | p.Gly363Ser | missense_variant, NMD_transcript_variant | 10/68 | ||||
FBN1 | ENST00000537463.6 | c.636+16992G>A | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251276Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135812
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727234
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74324
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 06, 2023 | This missense variant replaces glycine with serine at codon 363 of the FBN1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282662 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. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 21, 2023 | This missense variant replaces glycine with serine at codon 363 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 11/282662 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 | Mayo Clinic Laboratories, Mayo Clinic | Jun 17, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; 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) Collod-Beroud G et al. (2003) Hum Mutat 22 (3):199-208 (PMID: 12938084); This variant is associated with the following publications: (PMID: 19370756) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 363 of the FBN1 protein (p.Gly363Ser). This variant is present in population databases (rs363855, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576755). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at