ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7964C>T (p.Ala2655Val) (rs202240409)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724342 SCV000231913 uncertain significance not provided 2014-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000179634 SCV000718147 likely benign not specified 2017-11-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179634 SCV001337957 likely benign not specified 2020-01-19 criteria provided, single submitter clinical testing Variant summary: FBN1 c.7964C>T (p.Ala2655Val) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 253322 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 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 South Asian origin. c.7964C>T has been reported in the literature in sequencing studies of Finnish patients with HCM (Jaaskelainen_2019) and in individuals who did not fulfill the revised Ghent 2010 nosology for Marfan syndrome (Baudhuin_2015). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV001180301 SCV001345196 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-11-18 criteria provided, single submitter clinical testing
Invitae RCV001475865 SCV001680063 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-11-01 criteria provided, single submitter clinical testing

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