ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.185G>A (p.Arg62His)

gnomAD frequency: 0.00012  dbSNP: rs145942328
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000757273 SCV000058770 uncertain significance not provided 2022-11-03 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000777703 SCV000738792 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-08-09 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757273 SCV000885429 uncertain significance not provided 2017-08-28 criteria provided, single submitter clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000035130 SCV000891639 uncertain significance Marfan syndrome 2017-12-30 criteria provided, single submitter curation
Color Diagnostics, LLC DBA Color Health RCV000777703 SCV000913646 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-02-16 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781355 SCV000919330 uncertain significance not specified 2023-08-14 criteria provided, single submitter clinical testing 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.
Invitae RCV001046446 SCV001210350 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000757273 SCV001815271 uncertain significance not provided 2020-10-15 criteria provided, single submitter clinical testing 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)
Mendelics RCV000781355 SCV002517074 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000035130 SCV004823147 uncertain significance Marfan syndrome 2023-12-01 criteria provided, single submitter clinical testing 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.
University of Washington Center for Mendelian Genomics, University of Washington RCV000755193 SCV000883022 uncertain significance Congenital aneurysm of ascending aorta; Acute aortic dissection 2016-01-20 no assertion criteria provided research

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