rs727503172

Positions:

• chr11-47333235-GC-G

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.3288delG​(p.Glu1096fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1096E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.00300

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 11-47333235-GC-G is Pathogenic according to our data. Variant chr11-47333235-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 164042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333235-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3288delG	p.Glu1096fs	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.3288delG	p.Glu1096fs	frameshift_variant	30/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3288delG	p.Glu1096fs	frameshift_variant	29/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Glu1096Aspfs*93) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 2732257, 16679492, 21750094, 24510615). ClinVar contains an entry for this variant (Variation ID: 164042). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2014	The p.Glu1096fs variant in MYBPC3 has been identified in 5 individuals with HCM (Lekanne Deprez 2006, Kapplinger 2014, LMM unpublished data). It was absent from large population studies. This variant is predicted to cause a frameshift, whic h alters the protein?s amino acid sequence beginning at position 1096 and lead t o a premature termination codon 93 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria to be classified as pathogenic (http://www.partn ers.org/personalizedmedicine/LMM) based upon the predicted impact of the variant . -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 27, 2024	This variant deletes 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. This variant has been reported in at least five individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 24793961, 25611685, 27532257, 30297972, 30847666). It has also been reported in compound heterozygous state with another pathogenic truncation variant in the MYBPC3 gene in one infant affected with severe neonatal hypertrophic cardiomyopathy (PMID: 16679492). This variant has not been identified 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:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2024	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; Published RNA studies demonstrate mRNA nonsense mediated decay and absence of protein (PMID: 16679492); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30847666, 21750094, 16679492, 27532257, 24510615) -

Hypertrophic cardiomyopathy 4 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 07, 2021	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 04, 2017

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 01, 2020

Variant summary: MYBPC3 c.3288delG (p.Glu1096AspfsX93) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 210992 control chromosomes. c.3288delG has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (examples- Lekanne_2006, Waldmuller_2011, Kapplinger_2014, Bos_2014, Walsh_2017, van Lint_2019). These data indicate that the variant is very likely to be associated with disease, however at least one publication reports the variant in an unaffected individual, suggesting imcomplete penetrance (Lekanne_2006). One publication reports that mRNA with the variant could not be detected in the peripheral blood of a patient with this mutation, indicating nonsense-mediated decay (Lekanne_2006). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2016

The c.3288delG pathogenic mutation, located in coding exon 30 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3288, causing a translational frameshift with a predicted alternate stop codon (p.E1096Dfs*93). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Lekanne Deprez RH et al. J. Med. Genet., 2006 Oct;43:829-32; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61). 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)		0.0		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: rs727503172; hg19: chr11-47354786;