rs730880652

Positions:

• chr11-47337533-CCGCAT-C

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.2455_2459del​(p.Met819AlafsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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:4
• Conservation: PhyloP100: 7.67

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 11-47337533-CCGCAT-C is Pathogenic according to our data. Variant chr11-47337533-CCGCAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 181079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337533-CCGCAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2455_2459del	p.Met819AlafsTer12	frameshift_variant	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2455_2459del	p.Met819AlafsTer12	frameshift_variant	25/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2455_2459del	p.Met819AlafsTer12	frameshift_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.2414-27_2414-23del		intron_variant, NMD_transcript_variant		5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29121657, 37652022, 15519027) -

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.2455_2459delATGCG (p.Met819AlafsX12) 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 249218 control chromosomes. c.2455_2459delATGCG has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (example, Van Driest_2004, Viswanathan_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2022

This variant is also known as W818 fs/11. This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 29121657). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met819Alafs*12) 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). ClinVar contains an entry for this variant (Variation ID: 181079). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.2455_2459delATGCG pathogenic mutation, located in coding exon 25 of the MYBPC3 gene, results from a deletion of 5 nucleotides at nucleotide positions 2455 to 2459, causing a translational frameshift with a predicted alternate stop codon (p.M819Afs*12). This alteration, referred to as W818 fs/11, has been reported in a cohort of individuals with hypertrophic cardiomyopathy (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880652; hg19: chr11-47359084;