ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3712G>A (p.Asp1238Asn) (rs794728208)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181493 SCV000233796 pathogenic not provided 2015-05-14 criteria provided, single submitter clinical testing p.Asp1238Asn (GAC>AAC): c.3712 G>A (NM_000138.4)The D1238N mutation has been reported in association with Marfan syndrome (Yuan B et al. 1999). This mutation affects the first Aspartic acid of a cbEGF domain in FBN1, a position where the negatively charged Aspartic Acid is necessary to bind a positively charged calcium ion (Hilhorst-Hofstee Y et al., 2010). A different missense mutation at the same position, D1238G, has also been reported in association with Marfan syndrome (Tiecke F et al., 2001). The D1238N mutation results in a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The D1238 residue is conserved across species. The D1238N mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The variant is found in TAAD panel(s).
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659532 SCV000781359 likely pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763355 SCV000894045 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,University Medical Center Hamburg-Eppendorf RCV000659532 SCV000897663 pathogenic Marfan syndrome 2018-11-20 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000181493 SCV000927424 likely pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
Invitae RCV000808826 SCV000948948 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-06-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1238 of the FBN1 protein (p.Asp1238Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 30 of the FBN1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 10533071, Invitae). ClinVar contains an entry for this variant (Variation ID: 200022). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001176349 SCV001340313 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-12-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192801 SCV001361161 uncertain significance not specified 2019-10-08 criteria provided, single submitter clinical testing Variant summary: FBN1 c.3712G>A (p.Asp1238Asn) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the last 3' position of exon 30, therefore, suggesting the variant could affect splicing. Several computational tools predict a suggestive impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3712G>A has been reported in the literature in individuals affected with Marfan Syndrome and aortopathies and related disorders of connective tissue (De Cario_2018, Yuan_1999, Renner_2019). Hicks_2018 reports a 15 y/o female that presented with no phenotypic representation, however, had a family history. These report(s) 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. However, HGMD reports another missense variant at this location, D1238N, associated with Marfan syndrome. Seven ClinVar submissions (evaluation after 2014) cites the variant three times as pathogenic, three times as likely pathogenic, and once as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000659532 SCV000786990 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.