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

gnomAD frequency: 0.00012  dbSNP: rs145942328

Total submissions: 11

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	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-05-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-07-24	criteria provided, single submitter	clinical testing	Has been previously observed in individuals referred for Marfan or Marfan-like syndromes and in a patient with tricuspid aortic valve (PMID: 24793577, 26621581, 29357934); Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24793577, 22102435, 26621581, 12938084, 29357934, 37937776, 28659821)
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