ClinVar Miner

Submissions for variant NM_005585.5(SMAD6):c.362G>A (p.Cys121Tyr)

gnomAD frequency: 0.00101  dbSNP: rs80232004
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000501747 SCV000597170 likely benign not specified 2016-08-19 criteria provided, single submitter clinical testing
Invitae RCV000550166 SCV000650589 benign Aortic valve disease 2 2024-01-20 criteria provided, single submitter clinical testing
New York Genome Center RCV001263405 SCV001441449 uncertain significance Bicuspid aortic valve 2019-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501747 SCV004803957 likely benign not specified 2024-01-29 criteria provided, single submitter clinical testing Variant summary: SMAD6 c.362G>A (p.Cys121Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 1231328 control chromosomes, predominantly at a frequency of 0.013 within the Latino subpopulation in the gnomAD database v4. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 415.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.362G>A in individuals affected with Aortic Valve Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 436796). Based on the evidence outlined above, the variant was classified as likely benign.

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