rs730880666

Positions:

• chr11-47333667-TC-TTT

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.3079delGinsAA​(p.Asp1027fs) variant causes a frameshift, missense 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: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.56

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 11-47333668-C-TT is Pathogenic according to our data. Variant chr11-47333668-C-TT is described in ClinVar as [Pathogenic]. Clinvar id is 181093.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.3079delGinsAA	p.Asp1027fs	frameshift_variant, missense_variant	29/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3079delGinsAA	p.Asp1027fs	frameshift_variant, missense_variant	29/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3079delGinsAA	p.Asp1027fs	frameshift_variant, missense_variant	28/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 05, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2014

Although the c.3079delinsAA variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Aspartic acid 1027, changing it to a Lysine, and creating a premature stop codon at position 24 of the new reading frame, denoted p.Asp1027LysfsX24. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with cardiomyopathy. Furthermore, the c.3079delinsAA variant 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. In summary, c.3079delinsAA in the MYBPC3 gene is interpreted as a pathogenic variant. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2021

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with MYBPC3-related conditions. This sequence change creates a premature translational stop signal (p.Asp1027Lysfs*24) 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). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.3079delGinsAA pathogenic mutation, located in coding exon 29 of the MYBPC3 gene, results from the deletion of one nucleotide and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.D1027Kfs*24). This variant has been detected in individuals or cohorts reported to have hypertrophic cardiomyopathy (Ho CY et al. Nat Med. 2021 Oct;27(10):1818-1824; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: rs730880666; hg19: chr11-47355219;