15-48490003-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_000138.5(FBN1):c.2930T>G(p.Met977Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,004 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M977V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.2930T>G | p.Met977Arg | missense_variant | 25/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.2930T>G | p.Met977Arg | missense_variant | 24/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.2930T>G | p.Met977Arg | missense_variant | 25/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727246
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152114Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74290
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2021 | Has been reported in a patient and his father with an FBN1-associated phenotype (Baudhuin et al., 2015); however the patient did not meet Ghent criteria and the variant did not track with all clinically affected members of this family.; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 195848; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25652356, 12938084, 26582918) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | FBN1: PP2, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2014 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 2021 | The p.M977R variant (also known as c.2930T>G), located in coding exon 24 of the FBN1 gene, results from a T to G substitution at nucleotide position 2930. The methionine at codon 977 is replaced by arginine, an amino acid with similar properties, and is located in the TGFBP #03 domain. This alteration was reported in a subject with features of Marfan syndrome who did not meet Ghent criteria (Baudhuin LM et al. J Hum Genet, 2015 May;60:241-52). This amino acid position is 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 | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This missense variant replaces methionine with arginine at codon 977 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 reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25652356). This variant has been identified in 4/251462 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. - |
Marfan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This missense variant replaces methionine with arginine at codon 977 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 reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25652356). This variant has been identified in 4/251462 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. - |
FBN1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 17, 2019 | The FBN1 c.2930T>G (p.Met977Arg) variant is a missense variant that has been reported in a heterozygous state in a 7-year-old Caucasian male with a suspected diagnosis of Marfan syndrome who was above the 95th percentile for height and showed mild hypotonia and hyperreflexivity but did not meet the revised Ghent criteria (Baudhuin et al. 2015). The variant was also found in his 46-year-old father, who showed tall stature, joint hypermobility, pectus excavatum, and underwent aortic graft. However, a paternal male cousin, who showed wrist and thumb signs, joint hypermobility, highly arched palate, and crowded teeth, did not carry the p.Met977Arg variant, suggesting it did not segregate with the phenotype in this family. The variant is reported at a frequency of 0.000016 in the Total population of the Genome Aggregation Database. Functional studies of this variant, which is located in a TGFβ binding-protein-like domain, have not been conducted, and in silico tools vary in their predictions of its effect. Based on the limited evidence available, the p.Met977Arg variant is classified as of unknown significance for FBN1-related disorders. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 977 of the FBN1 protein (p.Met977Arg). This variant is present in population databases (rs199682686, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 25652356). ClinVar contains an entry for this variant (Variation ID: 195848). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
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 | Oct 12, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at