ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2737+5G>A (rs398123280)

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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 RCV000078450 SCV000110303 uncertain significance not provided 2015-09-16 criteria provided, single submitter clinical testing
Invitae RCV000474107 SCV000546446 likely pathogenic Hypertrophic cardiomyopathy 2020-09-24 criteria provided, single submitter clinical testing This sequence change falls in intron 26 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein, but it affects a nucleotide within the consensus splice site of the intron. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972, Invitae). ClinVar contains an entry for this variant (Variation ID: 92690). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000618232 SCV000737355 likely pathogenic Cardiovascular phenotype 2020-06-03 criteria provided, single submitter clinical testing The c.2737+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 26 in the MYBPC3 gene. This alteration has been reported in multiple unrelated probands with hypertrophic cardiomyopathy (HCM) (Ho CY et al. Circulation, 2018 Oct;138:1387-1398; GeneDx pers. comm.; Invitae pers. comm.; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder in silico models, this alteration is predicted to decrease the efficiency of the native splice donor site; however experimental evidence is not currently available. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001184227 SCV001350167 uncertain significance Cardiomyopathy 2019-07-27 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000078450 SCV001713561 likely pathogenic not provided 2019-07-08 criteria provided, single submitter clinical testing PVS1_moderate, PM2, PS4_moderate

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