ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.3979-8_3979-7delinsGC (rs727503235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151214 SCV000199054 uncertain significance not specified 2014-06-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The 3979-8_3979-7de linsGC in MYH6 has been identified by our laboratory in 2 adults with DCM +/- co nduction system disease. Data from large populations studies is insufficient to assess the frequency of this variant. This region of intron 28 includes a homopo lymer region with a string of C divided by a single T and is highly variable wit h multiple variations on this sequence having been identified. Due the variabili ty that has been seen in this region and because the MYH6 gene has not yet been strongly associated with cardiomyopathy, this variant is less likely to contribu te to disease. In summary, though its clinical significance is uncertain, the va riation in this region suggests that it is more likely to be benign.
Invitae RCV000228002 SCV000287417 likely benign not provided 2018-09-04 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769402 SCV000900794 uncertain significance Cardiomyopathy 2015-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000151214 SCV000919826 likely benign not specified 2018-05-09 criteria provided, single submitter clinical testing Variant summary: MYH6 c.3979-8_3979-7delinsGC 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. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Both gnomAD and ExAC list two independent variants, c.3979-8C>G and c.3979-7T>C, opposed to delins, however, based on the raw data provided, both variants are frequently observed in cis, predominantly in African control individuals, forming c.3979-8_3979-7delinsGC. The observed variant frequency within African control individuals in the gnomAD database is significantly higher the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.3979-8_3979-7delinsGC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as Likely benign.

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