rs794728162
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.640G>A(p.Gly214Ser) 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. 11/18 in silico tools predict a damaging 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. G214D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.640G>A | p.Gly214Ser | missense_variant | 7/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.640G>A | p.Gly214Ser | missense_variant | 6/65 | ||
FBN1 | NM_001406717.1 | c.640G>A | p.Gly214Ser | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.640G>A | p.Gly214Ser | missense_variant | 7/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.640G>A | p.Gly214Ser | missense_variant, NMD_transcript_variant | 7/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.640G>A | p.Gly214Ser | missense_variant, NMD_transcript_variant | 7/68 | ||||
FBN1 | ENST00000537463.6 | c.636+4G>A | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PS1, PP4 - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Medical Center Hamburg-Eppendorf | Nov 20, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2018 | The p.G214S pathogenic mutation (also known as c.640G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 640. The glycine at codon 214 is replaced by serine, an amino acid with similar properties. This mutation was initially described in a Chinese family with ectopia lentis and was reported to segregate with disease in affected family members (Sui RF et al. Zhonghua Yan Ke Za Zhi, 2004 Dec;40:828-31). Subsequently, this mutation has been described in multiple individuals with Marfan syndrome (MFS) from a variety of ethnic backgrounds, including one large family with segregation in 13 family members with MFS (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Dong J et al. Mol. Vis., 2012 Jan;18:81-6; Franken R et al. Eur. Heart J., 2016 11;37:3285-3290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2017 | Variant summary: The FBN1 c.640G>A (p.Gly214Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the first TB domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121464 control chromosomes). The variant has been found to segregate with classical Marfan syndrome within a four-generation nonconsanguineous Chinese family (Dong_Mol Vis_2012). It has also been identified in patients with Marfan syndrome or Marfan-related disorders (Stheneur_EJHG_2009; Franken_Euro Heart J_2016). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 22, 2019 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 214 of the FBN1 protein (p.Gly214Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis, Marfan syndrome, aortopathy and thoracic aortic aneurysms and dissections (PMID: 15733436, 17657824, 22262941, 22772377, 26787436, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199956). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at