ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2746G>A (p.Val916Met) (rs373644734)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181468 SCV000233770 uncertain significance not provided 2013-06-14 criteria provided, single submitter clinical testing p.Val916Met (GTG>ATG): c.2746 G>A in exon 24 of the FBN1 gene (NM_000138.4)The Val916Met variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val916Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Val916Met is probably damaging to the protein structure/function. Mutations in nearby codons (Glu913Gly, Cys914Ser, Glu915Lys, Cys921Gly) have been reported in association with Marfan syndrome/fibrillinopathy, supporting the functional importance of this region of the protein. The Val916Met variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.With the clinical and molecular information available at this time, we cannot definitively determine if Val916Met is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000780231 SCV000917338 likely benign not specified 2018-02-03 criteria provided, single submitter clinical testing Variant summary: FBN1 c.2746G>A (p.Val916Met) results in a conservative amino acid change located in the cb EGF-like #10 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 0.000047 in 13/277068 control chromosomes, predominantly at a frequency of 0.00042 (10/24014 chrs) within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The c.2746G>A has been reported in the literature in at least one individual with adolescent idiopathic scoliosis (Buchan_2014). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000631996 SCV000753099 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 916 of the FBN1 protein (p.Val916Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs373644734, ExAC 0.05%). This variant has been reported in an individual affected with idiopathic scoliosis (PMID: 24833718). ClinVar contains an entry for this variant (Variation ID: 200004). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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