ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.926+1G>A

gnomAD frequency: 0.00001  dbSNP: rs767239679
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000614824 SCV000731494 uncertain significance not specified 2019-08-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.926+1G>A variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy but has been identified in 3/27668 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP3.
Color Diagnostics, LLC DBA Color Health RCV001179403 SCV001344058 uncertain significance Cardiomyopathy 2023-11-13 criteria provided, single submitter clinical testing This variant causes a C>T nucleotide substitution at the +1 position of intron 11 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Because this variant alters the canonical splice donor site, it is expected to cause an in-frame skipping of 27 nucleotides (9 amino acids). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 3/231142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001860337 SCV002300638 likely pathogenic Hypertrophic cardiomyopathy 2021-08-05 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 517283). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (Invitae). This variant is present in population databases (rs767239679, ExAC 0.02%). This sequence change affects a donor splice site in intron 11 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).

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