ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2556_2557delinsTCT (p.Gly853fs) (rs397515975)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000546675 SCV000059157 pathogenic Hypertrophic cardiomyopathy 2018-12-07 criteria provided, single submitter clinical testing The p.Gly853LeufsX31 variant in MYBPC3 has been identified in 7 Caucasian indivi duals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 af fected relatives from one family, including 1 affected obligate carrier (Morner 2003, Walsh 2017). In addition, this variant has been identified by our laborato ry in 2 adults with HCM, and was absent from large population studies, though th e ability of these studies to accurately detect indels may be limited. This vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 853 and leads to a premature termination codon 31 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this va riant meets criteria to be classified as pathogenic for HCM in an autosomal domi nant manner based upon the predicted impact on the protein, its absence from the general population, segregation studies and presence in multiple affected indiv iduals. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1, PM2.
GeneDx RCV000158369 SCV000208304 pathogenic not provided 2017-07-29 criteria provided, single submitter clinical testing The c.2556_2557delCGinsTCT pathogenic variant in the MYBPC3 gene has been previously reported in multiple individuals in association with HCM, and has been denoted in published literature as c.2556_2557delinsTCT (p.Gly853fs), ins t, ggc>tgc (A851 fs/31), and delCG/insTCT 852, due to alternate nomenclature (Morner et al., 2003; Van Driest et al., 2004; Walsh et al., 2017). This variant was also shown to segregate with HCM in four affected relatives from one Swedish family, and haplotype analysis of three unrelated Swedish probands with HCM who harbored c.2556_2557delCGinsTCT suggests it may be a founder mutation in this population (Morner et al., 2003). Additionally, this variant is classified in ClinVar as a pathogenic variant by other clinical laboratories (ClinVar SCV000059157.4; SCV000264056.1; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon glycine 853, changing it to a leucine, and creating a premature stop codon at position 31 of the new reading frame, denoted p.Gly853LeufsX31. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, multiple other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Finally, the c.2556_2557delCGinsTCT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Blueprint Genetics RCV000208351 SCV000264056 pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-22 criteria provided, single submitter clinical testing
Invitae RCV000546675 SCV000623564 pathogenic Hypertrophic cardiomyopathy 2019-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly853Leufs*31) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is reported as two separate entries in the ExAC population database (c.2555dup, 0.002% and c.2557G>T, 0.002%). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family (PMID: 12818575) and has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 12818575, 27532257, 24510615). This variant is also known as del CG, insTCT 852 in the literature. ClinVar contains an entry for this variant (Variation ID: 42639). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000590598 SCV000696324 pathogenic Cardiovascular phenotype 2016-03-24 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158369 SCV000927193 pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing

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