ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3782_3792delinsCCTG (p.Glu1261fs)

dbSNP: rs1085307897
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489121 SCV000577619 likely pathogenic not provided 2016-03-08 criteria provided, single submitter clinical testing A c.3782_3792del11insCCTG likely pathogenic variant was identified in the MYBPC3 gene. Although the c.3782_3792del11insCCTG variant has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Glutamic acid 1261, changing it to an Alanine, and creating a premature stop codon at position 68 of the new reading frame, denoted p.Glu1261AlafsX68. This variant, occurring in an immunoglobulin-like C2-type domain, replaces the last 14 amino acids with 67 new amino acids, likely disrupting this domain. Other frameshift variants in the MYBPC3 gene resulting in extended protein length or missense/nonsense changes occurring within the last 14 amino acid have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.3782_3792del11insCCTG variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, this variant is likely pathogenic.
Ambry Genetics RCV002367665 SCV002625778 likely pathogenic Cardiovascular phenotype 2016-04-05 criteria provided, single submitter clinical testing The c.3782_3792del11insCCTG variant, located in coding exon 33 of the MYBPC3 gene, results from the deletion of 11 nucleotides and insertion of 4 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.E1261Afs*68). This variant results in a frameshift which replaces the last 15 amino acids with 68 aberrant amino acids at the 3' terminus of MYBPC3, elongating the protein. Per ACMG guidelines this variant could be interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294); however this deletion, insertion and subsequent frameshift occur near the 3' terminus of MYBPC3 and result in the elongation of the protein by 53 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6168 samples (12336 alleles) with coverage at this position. Based on the majority of available evidence to date, and since frameshifts are typically deleterious in nature, this alteration is likely to be pathogenic (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405-24).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000489121 SCV000924850 likely pathogenic not provided 2015-11-13 no assertion criteria provided provider interpretation Genetic testing: The patient had genetic testing for HCM. The test included sequencing of 18 genes associated with HCM: ACTC1, CAV3, GLA, LAMP2, MTTG, MTTI, MTTK ,MTTQ, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNC1, TNNI3, TNNT2, TPM1, TTR. Results show that a variant was found: p.Glu1261AlafsX68 (c.3782_3792del11insCCTG) in the MYBPC3 gene. The lab classifies this variant as a variant, likely disease-causing. Given that this variant is a deletion of 11 base pairs and insertion of 4 base pairs, which changes a glutamic acid to an alanine and creates a frameshift that replaces the last 14 amino acids with 67 new amino acids, we consider this variant pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This is a novel variant that has not been reported in any previous cases. In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6,157 Caucasian and African American individuals (as of 11/13/15). However, within the same region, there is a missense variant at p.R1263W that is reported as possibly damaging. There are no insertions or deletions within this region in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 11/13/15). However, there is a missense variant, p.Glu1261Lys that is listed as a variant of uncertain significance. There are no pathogenic variants listed in ClinVar within this region.

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