ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6164-3C>T (rs571365493)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181557 SCV000233860 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing c.6164-3 C>T: IVS50-3 C>T in intron 50 of the FBN1 gene (NM_000138.4)The c.6164-3 C>T variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. One in silico splice prediction algorithm predicts c.6164-3 C>T destroys or severely damages the natural splice acceptor site of intron 50, however a different algorithm predicts c.6164-3 C>T has no effect on splicing. Other splice site mutations in the FBN1 gene have been reported in association with Marfan syndrome. The c.6164-3 C>T variant 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.With the clinical and molecular information available at this time, we cannot definitively determine if c.6164-3 C>T is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae RCV000549219 SCV000627956 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2017-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620610 SCV000738825 uncertain significance Cardiovascular phenotype 2016-07-27 criteria provided, single submitter clinical testing The c.6164-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 50 in the FBN1 gene. This variant was previously reported in the SNPDatabase as rs571365493. Based on data from ExAC, the T allele has an overall frequency less than 0.01% (9/106090). This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This nucleotide position is well conserved in available vertebrate species; however, T is the reference nucleotide in other vertebrate species. This alteration is predicted by the ESEfinder in silico splicing model to weaken the efficiency of the native splice acceptor site, but is not predicted to have a significant effect on the native splice acceptor site by the BDGP or the Human Splicing Finder (HSF) in silico splicing models (Desmet FO et al. Nucleic Acids Res. 2009 May;37(9):e67); however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000777847 SCV000913849 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-10-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000181557 SCV001361377 likely benign not specified 2019-07-08 criteria provided, single submitter clinical testing Variant summary: FBN1 c.6164-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 251030 control chromosomes, predominantly at a frequency of 0.00029 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.6164-3C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics RCV001333241 SCV001525771 uncertain significance Marfan syndrome 2018-02-05 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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