ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3410G>A (p.Arg1137His)

gnomAD frequency: 0.00002  dbSNP: rs137854456
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000659525 SCV000781351 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001182733 SCV001348290 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-10-20 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1137 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: 31098894). This variant has been identified in 12/282874 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.
Invitae RCV001360976 SCV001556932 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-11-08 criteria provided, single submitter clinical testing
GeneDx RCV001538393 SCV001756039 uncertain significance not provided 2022-06-22 criteria provided, single submitter clinical testing Identified in association with aortic aneurysm/dissection in published literature (Li et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; 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: 31098894)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002235656 SCV002511396 uncertain significance not specified 2022-04-05 criteria provided, single submitter clinical testing Variant summary: FBN1 c.3410G>A (p.Arg1137His) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251474 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (4e-05 vs 0.00011), allowing no conclusion about variant significance. c.3410G>A has been reported in the literature in cis with another FBN1 variant (p.C2528Y) in an individual affected with Marfan Syndrome (Li_2019). Furthermore, c.3410G>A has been reported in a proband with systemic sclerosis but it was also found in the probands unaffected sibling and daughter (Tan_2001). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002499136 SCV002814953 uncertain significance Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome 2021-07-02 criteria provided, single submitter clinical testing

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