rs397516008

Variant names:

• chr11-47333297-T-TA
• rs397516008
• NM_000256.3:c.3226_3227insT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3226_3227insT​(p.Asp1076ValfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,590,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.56

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47333297-T-TA is Pathogenic according to our data. Variant chr11-47333297-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 42694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3226_3227insT	p.Asp1076ValfsTer6	frameshift_variant	Exon 30 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3226_3227insT	p.Asp1076ValfsTer6	frameshift_variant	Exon 30 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3226_3227insT	p.Asp1076ValfsTer6	frameshift_variant	Exon 29 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1438018 Hom.: 0 Cov.: 34 AF XY: 0.00000421 AC XY: 3 AN XY: 713040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000586 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiomyopathy Pathogenic:2

Jun 30, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

Dec 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jun 06, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4 Pathogenic:2

Jul 02, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 27, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Oct 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Pathogenic:1

Nov 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516008; hg19: chr11-47354848;