rs145942328
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP2BS2
The NM_000138.5(FBN1):c.185G>A(p.Arg62His) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R62C) has been classified as Pathogenic.
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.185G>A | p.Arg62His | missense_variant | 3/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.185G>A | p.Arg62His | missense_variant | 2/65 | ||
FBN1 | NM_001406717.1 | c.185G>A | p.Arg62His | missense_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.185G>A | p.Arg62His | missense_variant | 3/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.185G>A | p.Arg62His | missense_variant, NMD_transcript_variant | 3/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.185G>A | p.Arg62His | missense_variant, NMD_transcript_variant | 3/68 | ||||
FBN1 | ENST00000537463.6 | c.185G>A | p.Arg62His | missense_variant, NMD_transcript_variant | 3/31 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249372Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135244
GnomAD4 exome AF: 0.0000370 AC: 54AN: 1461028Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29AN XY: 726800
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74280
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Arg62His variant in FBN1 has been identified in 1 individual with features of Marfan syndrome and 2 individuals with aortic aneurysm or dissection (Regalado 2016, Becerra-Muñoz 2018, LMM data). It has also been identified in 0.016% (4/24662) of African chromosomes by Genome Aggregation Databse (http://gnomad.broadinstitute.org). Arginine (Arg) at position 62 is not conserved in mammals or evolutionarily distant species and 6 mammals (marmoset, prairie vole, naked mole rat, guinea pig, chinchilla, brush tailed rat) carry a Histidine (His) at this position despite high nearby amino acid conservation, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Arg62His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4_Strong, PS4_Supporting. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 15, 2020 | Has been previously observed in individuals referred for Marfan or Marfan-like syndromes (Lerner-Ellis et al., 2014; Regalado et al., 2015; Becerra-Muoz et al., 2018).; 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 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); This variant is associated with the following publications: (PMID: 29357934, 26621581, 22102435, 24793577) - |
Marfan syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces arginine with histidine at codon 62 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 two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) and in a healthy individual as well (PMID: 28659821). This variant has been identified in 15/280762 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 specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2023 | Variant summary: FBN1 c.185G>A (p.Arg62His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249738 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FBN1 causing Marfan Syndrome (6e-05 vs 0.00011), allowing no conclusion about variant significance. c.185G>A has been reported in the literature in individuals affected with Marfan Syndrome (Lerner-Ellis_2014), isolated Thoracic Aneurism (Becerra-Munoz_2018; Regalado_2016) as well as in healthy individual without any cardiac abnormalities (Gillis_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24793577, 26621581, 29357934, 28659821). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely benign (n=1), or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2016 | The p.R62H variant (also known as c.185G>A), located in coding exon 2 of the FBN1 gene, results from a G to A substitution at nucleotide position 185. The arginine at codon 62 is replaced by histidine, an amino acid with highly similar properties, and is located in the 4-cys motif LTBP-like domain. This alteration was reported in a patient with Marfan syndrome (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6), as well as in one with thoracic aortic aneurysms and dissection (Regalado ES et al. Clin. Genet., 2016 Jun;89:719-23). This variant was previously reported in the SNPDatabase as rs145942328. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (6/105960). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12986) total alleles studied, having been observed in 0.02% (1/4394) African American alleles. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 16, 2023 | This missense variant replaces arginine with histidine at codon 62 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 two individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 26621581, 29357934 ) and in a healthy individual as well (PMID: 28659821). This variant has been identified in 15/280762 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. - |
Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Uncertain:1
Uncertain significance, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Jan 20, 2016 | - - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at