ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3330+5G>T (rs373746463)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248382 SCV000320270 likely pathogenic Cardiovascular phenotype 2015-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000158457 SCV000208392 pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing Although the c.3330+5 G>T variant has not been reported as a pathogenic variant or as a benign variant to ourknowledge, this nucleotidechange affects a conserved splice site in intron 30 of the MYBPC3 gene. In silico splice prediction algorithms predictthat the c.3330+5 G>T variant destroys the splice donor site in intron 30, leading to either an abnormal message thatis subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for proteintranslation. Other pathogenic variants affecting the same nucleotide (c.3330+5 G>A, c.3330+5 G>C), as well as otherdownstream splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database inassociation with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.3330+5 G>T variant was not observed inapproximately 6,200 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, nor was it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benignvariant in these populations.In summary, c.3330+5 G>T in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000793517 SCV000932873 likely pathogenic Hypertrophic cardiomyopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 30 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685). ClinVar contains an entry for this variant (Variation ID: 42707). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28679633). Different variants affecting this nucleotide (c.3330+5G>C and c.3330+5G>A) have been determined to be pathogenic (PMID: 28679633, 7493025, 25132132). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000793517 SCV000059232 likely pathogenic Hypertrophic cardiomyopathy 2012-06-14 criteria provided, single submitter clinical testing The 3330+5G>T variant in MYBPC3 has not been previously reported in the literatu re, but has been identified in 1 Caucasian individual and 1 Hispanic individual with HCM out of >3200 probands (>2150 Caucasian and >110 Hispanic) tested by our laboratory. This variant occurs in the 5' splice region. Computational tools su ggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. Another variant at the same position (3330+5G>C) has s hown segregation with disease and causes skipping of exon 30, resulting in a pre mature termination codon that is predicted to lead to a truncated or absent prot ein (Watkins 1995). This variant likely has a similar effect on splicing, but ad ditional studies are needed to establish this with confidence. In summary, addit ional evidence such as with disease and functional effects are required to fully establish the pathogenicity of this variant.

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