ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3764_3766CCA[1] (p.Thr1256del) (rs397516040)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506954 SCV000604329 likely pathogenic not specified 2017-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000158408 SCV000208343 likely pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing The c.3767_3769delCCA variant in the MYBPC3 gene has been reported in association with HCM (Bos et al., 2014; Coppini et al., 2014; Walsh et al., 2017; Weissler-Snir et al., 2017). This variant has been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx and was found to segregate with HCM in two affected relatives from one family. Furthermore, this variant is not observed in large population cohorts (Lek et al., 2016). The c.3767_3769delCCA variant results in an in-frame deletion of a threonine residue at codon 1256, denoted p.Thr1256del. While this in-frame deletion occurs at a residue that is not conserved across species, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Several other in-frame deletions in the MYBPC3 gene have been reported in the Human Mutation Database association with cardiomyopathy (Stenson et al., 2014). However, to our knowledge, no functional studies for c.3767_3769delCCA have been performed to determine the functional effect of this variant.
Invitae RCV000466712 SCV000546471 likely pathogenic Hypertrophic cardiomyopathy 2018-03-23 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 33 of the MYBPC3 mRNA (c.3767_3769delCCA). This leads to the deletion of 1 amino acid residue in the MYBPC3 protein (p.Thr1256del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 24793961). ClinVar contains an entry for this variant (Variation ID: 42741). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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 RCV000466712 SCV000059267 likely pathogenic Hypertrophic cardiomyopathy 2017-08-08 criteria provided, single submitter clinical testing The p.Thr1256del variant in MYBPC3 has been previously reported in at least 5 in dividuals with HCM and segregated with disease in 5 affected relatives (includin g 2 obligate carriers) from 1 family (Bos 2014, Coppini 2014; Weissler-Snir 2017 , LMM data). It has been reported in ClinVar (Variation ID:51911), but was absen t from large population studies. This variant is a deletion of one amino acid (T hr) at position 1256 and is not predicted to alter the protein reading-frame. In summary, although additional studies are required to fully establish its clinic al significance, the p.Thr1256del variant is likely pathogenic. ACMG/AMP Criteri a applied: PS4_Moderate; PP1_Moderate, PM2.

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