11-47333306-CG-CGG

Position:

• chr11-47333306-CG-CGG

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.3217dupC​(p.Arg1073fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.57

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 11-47333306-C-CG is Pathogenic according to our data. Variant chr11-47333306-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3217dupC	p.Arg1073fs	frameshift_variant	30/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3217dupC	p.Arg1073fs	frameshift_variant	30/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3217dupC	p.Arg1073fs	frameshift_variant	29/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 17, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg1073ProfsX4 Given the type of variant and its association with disease (reviewed below), we consider this variant likely disease-causing. The variant is novel. This variant is in exon 30 of the MYBPC3 gene. The duplication causes a shift in the reading frame starting at codon 1073 changing an Arginine to a Proline and creating a premature stop codon at position 4 of the new reading frame. This variant is expected to result in either an abnormal, truncated protein product or a loss of protein through nonsense-mediated mRNA decay. However there is no experimental data as of February 5, 2014 that demonstrates the truncated or absent protein product. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen ~6500 in individuals from publicly available population datasets. There is no variation of this type at codon 1073 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). p.R1073Q missense variant at this codon is reported in ESP in two African American individuals, and the p.R1073W variant is reported at this codon in one European individual. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/6/14). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 09, 2018	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2016	The p.Arg1073fs variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy. Data from large population studies is insufficient to ass ess the frequency of this variant. This variant is predicted to cause a frameshi ft, which alters the protein?s amino acid sequence beginning at position 1073 an d leads to a premature termination codon 4 amino acids downstream. This alterati on is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individua ls with HCM. In summary, this variant meets our criteria to be classified as pat hogenic for HCM in an autosomal dominant manner based upon the predicted impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30586709, 32815737). ClinVar contains an entry for this variant (Variation ID: 181096). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg1073Profs*4) 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). -

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: rs730880668; hg19: chr11-47354857;