ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.3462C>T (p.Ile1154=)

gnomAD frequency: 0.00004  dbSNP: rs144339604
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589547 SCV000695513 uncertain significance not specified 2023-06-26 criteria provided, single submitter clinical testing Variant summary: FBN1 c.3462C>T (p.Ile1154Ile) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 3.2e-05 in 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3462C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003444604 SCV000898696 likely benign Marfan syndrome 2022-08-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000806888 SCV000946909 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-10-24 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001185323 SCV001351512 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-08-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV001185323 SCV003863107 likely benign Familial thoracic aortic aneurysm and aortic dissection 2023-03-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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