rs397515960

Variant names:

• chr11-47337791-A-AC
• rs397515960
• NM_000256.3:c.2311dupG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2311dupG​(p.Val771GlyfsTer62) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.74
• Publications: 3 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47337791-A-AC is Pathogenic according to our data. Variant chr11-47337791-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 42615.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.2311dupG	p.Val771GlyfsTer62	frameshift_variant, splice_region_variant	Exon 24 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2311dupG	p.Val771GlyfsTer62	frameshift_variant, splice_region_variant	Exon 24 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2311dupG	p.Val771GlyfsTer62	frameshift_variant, splice_region_variant	Exon 23 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2311dupG		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:2

Aug 09, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The c.2311dupG pathogenic mutation, located in coding exon 24 of the MYBPC3 gene, results from a duplication of a guanine at nucleotide position 2311, causing a translational frameshift with a predicted alternate stop codon. Haploinsufficiency of MYBPC3 has been indicated as a mechanism of disease, causing hypertrophic cardiomyopathy (Marston et al. 2012 J Muscle Res Cell Motil 33:75-80). In addition, in one series analyzing MYBPC3 mutation types in patients with hypertrophic cardiomyopathy (HCM) compared to patients with dilated cardiomyopathy (DCM), mutations causing a frame-shift make up a greater proportion of mutations in HCM patients (26%) compared to DCM patients (2%). Authors also identified a statistically significant correlation between left atrial dilation and frame-shift alterations (Waldmuller et al. Eur J Heart Fail 2011;13:1185-1192). In addition to the data presented in the literature, premature stop codons are typically deleterious in nature and interpreted as disease-causing mutations (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Based on the supporting evidence, c.2311dupG is interpreted as a pathogenic mutation. -

Nov 27, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_mod, PM2, PP1, PP5 -

Cardiomyopathy Pathogenic:1

Jun 16, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val771GlyfsX62 (V771GfsX62) : c.2311dupG in exon 24 of the MYBPC3 gene (NM_000256.3). The normal sequence with the base that is inserted in braces is: gACG{G}TGCC with lower case letter representing intronic sequence and upper cases letters representing exonic sequence. Although the c.2311dupG mutation in the MYBPC3 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Valine 771, changing it to a Glycine, and creating a premature stop codon at position 62 of the new reading frame, denoted p.Val771GlyfsX62 het. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Additionally, c.2311dupG was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other frameshift mutations in the MYBPC3 gene have been reported in association with cardiomyopathy. The variant is found in MYBPC3 panel(s). -

not provided Pathogenic:1

May 28, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Mar 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val771GlyfsX62 variant in MYBPC3 has been reported in at least 3 individuals with hypertrophic cardiomyopathy (HCM) and 1 individual with suspected HCM (Walsh 2017 PMID: 27532257, Hathaway 2021 PMID: 33673806, LMM data) and by other clinical laboratories in ClinVar (Variation ID 42615). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 771 and leads to a premature termination codon 62 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, PM2_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397515960; hg19: chr11-47359342;