ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.551dup (p.Lys185fs) (rs397516059)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769360 SCV000900748 pathogenic Cardiomyopathy 2016-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000223779 SCV000208350 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing Although the c.551dupT pathogenic variant in the MYBPC3 gene has not been published to our knowledge, this variant causes a shift in reading frame starting at codon Lysine 185, changing it to a Glutamic acid, and creating a premature stop codon at position 56 of the new reading frame, denoted p.Lys185GlufsX56. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift pathogenic variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014).
Invitae RCV000467369 SCV000546494 pathogenic Hypertrophic cardiomyopathy 2018-02-09 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 5 of the MYBPC3 mRNA (c.551dupT), causing a frameshift at codon 185. This creates a premature translational stop signal (p.Lys185Glufs*56) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000467369 SCV000059297 pathogenic Hypertrophic cardiomyopathy 2015-08-13 criteria provided, single submitter clinical testing The p.Lys185fs variant in MYBPC3 has been previously identified by our laborator y in three Caucasian adults with HCM. It has not been identified in large popula tion studies, though the ability of these studies to detect indels accurately ma y be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 185 and leads to a premature termination codon 56 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the M YBPC3 gene is an established disease mechanism in individuals with HCM. In summa ry, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) ba sed upon the predicted impact of the variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000225364 SCV000280588 pathogenic Familial hypertrophic cardiomyopathy 4 2016-04-26 criteria provided, single submitter clinical testing p.Lys185GlufsTer55 (CTGAAG>CT{T}GAAG) : c.551dupT in exon 5 of the MYBPC3 gene (NM_000256.3). The variant Lys185GlufsTer55 (p.K185EfsX55) in the MYBPC3 gene has not been reported to our knowledge. However, it was observed in more than ten (10) unrelated families tested for HCM by the Molecular Diagnostics Laboratory of the Montreal Heart Institute. It meets the following criteria of pathogenicity of the ACMG : PVS1 : The duplication of a thymidine at position 551 causes a change in the reading frame for 55 amino acids and leads to a stop codon resulting in a shortened protein of 81%. This variant is expected to result in an abnormal product : a truncated protein or loss of protein production from this allele through nonsense-mediated accelerated decay of the mRNA. PM2 :Lys185GlufsTer55 was not reported in ExAC database (more than 120,000 alleles) and was not observed in the populations of the 1000 Genome Project (more than 5000 individuals) neither in the populations of European and African American ancestry in the NHLBI Exome Sequencing Project (more than 6500 individuals). This means it is not a common benign variant in these populations. PP5 :The variant was the subject of two submissions in ClinVar: both in pathogenic category. In summary, Lys185GlufsTer55 in the MYBPC3 gene combines a very strong criteria of pathogenicity, a moderate criteria and a supporting criteria. It is interpreted as pathogenic variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845403 SCV000987468 pathogenic Familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223779 SCV000280273 likely pathogenic not provided 2013-06-19 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Lys185GlufsX56 Based on the data reviewed below we consider this variant as likely disease-causing, based on the type of variant and gene. This variant is located in exon 5 of the MYPBC3 gene. This is a frameshift variant. The c.551dupT variant causes a shift in the reading frame at codon Lysine185, changing it to an Glutamic acid and creates a premature Stop codon at position 56 of the new reading frame. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. This variant is novel. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6.500 Caucasian and African American individuals (as of 1/3/14). This variant has not been reported in dbSNP or 1000Genomes. GeneDx did not report control data.

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