rs397515960

chr11-47337791-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):c.2311_2312insG(p.Val771GlyfsTer62) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.74

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 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/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2311_2312insG	p.Val771GlyfsTer62	frameshift_variant	24/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2311_2312insG	p.Val771GlyfsTer62	frameshift_variant	24/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2311_2312insG	p.Val771GlyfsTer62	frameshift_variant	23/34	5		A2
MYBPC3	ENST00000544791.1	c.2311_2312insG	p.Val771GlyfsTer37	frameshift_variant, NMD_transcript_variant	24/27	5

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

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2014

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

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 28, 2018

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 26, 2017

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2022

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2013

​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. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515960; hg19: chr11-47359342;