rs727503186

chr11-47337436-CG-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.2556del(p.Ile852MetfsTer27) 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. I852I) has been classified as Likely 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:3
• Conservation: PhyloP100: -0.0750

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 11-47337436-CG-C is Pathogenic according to our data. Variant chr11-47337436-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 164071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337436-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2556del	p.Ile852MetfsTer27	frameshift_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2556del	p.Ile852MetfsTer27	frameshift_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2556del	p.Ile852MetfsTer27	frameshift_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*61del		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Ile852Metfs*27) 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: 12707239, 26914223). This variant is also known as Del C16212. ClinVar contains an entry for this variant (Variation ID: 164071). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 16, 2013	The Ile852fs variant in MYBPC3 has been reported in 1 individual with HCM (Richa rds 2003). This frameshift variant is predicted to alter the protein?s amino aci d sequence beginning at position 852 and lead to a premature termination codon 2 7 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Truncating variants in MYBPC3 are established as pathogeni c for HCM. In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) based on the predicted impact of the varia nt. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2012

The c.2556delC variant in the MYBPC3 gene has been reported in association with HCM (Richard P et al., 2003). Richard et al. identified c.2556delC (reported as del C16212 using alternative nomenclature) in one patient with HCM, and the mutation was absent in 200 control chromosomes. The c.2556delC variant causes a shift in the reading frame starting at codon Isoleucine 852, changing it to a Methionine, and creates a premature stop codon at position 27 of the new reading frame. This variant is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. Therefore, c.2556delC in the MYBPC3 gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727503186; hg19: chr11-47358987;