Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42694; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28152038, 24510615, 24793961, 25611685, 26688388, 25031304, 20800588, 24721642, 27532257, 20474083, 31006259, 30550750, 33087929)

This variant inserts 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause mislocalization of the MYBPC3 protein within the sarcomere and decreased incorporation into myofilament (DOI:10.1161/circ.130.suppl_2.20311). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 25031304, 25611685, 27532257, 31006259, 32841044, 33495596, 33495597). It has also been reported in individuals affected with dilated cardiomyopathy (PMID: 20474083). This variant has been identified in 1/31354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This variant inserts 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause mislocalization of the MYBPC3 protein within the sarcomere and decreased incorporation into myofilament (DOI:10.1161/circ.130.suppl_2.20311). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 25031304, 25611685, 27532257, 31006259, 32841044, 33495596, 33495597). It has also been reported in individuals affected with dilated cardiomyopathy (PMID: 20474083). This variant has been identified in 1/31354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.Asp1076ValfsX6 variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 3 affected individuals from 3 families (Bos 2014, Kapplinger 2014, Walsh 2017, LMM data). It has also been identified in 1/15396 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1076 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1.

The MYBPC3 c.3226_3227insT (p.Asp1076Valfs*6) variant has been reported in several individuals with cardiomyopathy (Zimmerman RS et al., PMID: 20474083; Kapplinger JD et al., PMID: 24510615; Helms AS et al., PMID: 25031304; Alfares AA et al., PMID: 25611685; Walsh R et al., PMID: 27532257). This variant has been reported in the ClinVar database as pathogenic by multiple submitters (ClinVar Variation ID: 42694). This variant is only observed on 6/1,590,162 alleles in the general population (gnomAD v4.0.0), indicating it is not a common variant. This variant causes a frameshift by inserting 1 nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Loss-of-function variants in MYBPC3 are known to be pathogenic (Marston S et al., PMID: 19574547). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the MYBPC3 c.3226_3227insT (p.Asp1076Valfs*6) variant is classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (N) 0201 - Variant is located in exon 30 of 35 and is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD v3 <0.001 (1 heterozygote, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with hypertrophic cardiomyopathy (ClinVar, PMID: 27532257). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Variant summary: MYBPC3 c.3226_3227insT (p.Asp1076ValfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 210750 control chromosomes. c.3226_3227insT has been reported in the literature in at-least one individual affected with Hypertrophic Cardiomyopathy (example: OLeary_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20474083, 20851114, 30550750). ClinVar contains an entry for this variant (Variation ID: 42694). Based on the evidence outlined above, the variant was classified as pathogenic.

The c.3226_3227insT pathogenic mutation, located in coding exon 30 of the MYBPC3 gene, results from an insertion of one nucleotide at position 3226, causing a translational frameshift with a predicted alternate stop codon (p.D1076Vfs*6). This variant was reported in individuals or cohorts with features consistent with hypertrophic cardiomyopathy (Bos JM et al. Mayo Clin Proc. 2014;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This sequence change creates a premature translational stop signal (p.Asp1076Valfs*6) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with cardiomyopathy (PMID: 20474083, 24510615, 25031304, 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42694). For these reasons, this variant has been classified as Pathogenic.