rs397516032

chr11-47350545-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.362del(p.Pro121ArgfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,552,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P121P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.77

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 11-47350545-CG-C is Pathogenic according to our data. Variant chr11-47350545-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 42729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.362del	p.Pro121ArgfsTer38	frameshift_variant	3/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.362del	p.Pro121ArgfsTer38	frameshift_variant	3/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.362del	p.Pro121ArgfsTer38	frameshift_variant	3/34	5		A2
MYBPC3	ENST00000544791.1	c.362del	p.Pro121ArgfsTer38	frameshift_variant, NMD_transcript_variant	3/27	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400326 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 693990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 30, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42729). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 30297972). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro121Argfs*38) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 22, 2012	The Pro121fs variant in MYBPC3 has not been reported in the literature, but has been identified in 1 individual with HCM (this individual) out of >3600 individu als (>2200 Caucasian) tested by our laboratory (LMM unpublished data). This fram eshift variant is predicted to alter the protein?s amino acid sequence beginning at position 121 and lead to a premature termination codon 38 amino acids downst ream. This alteration is then predicted to lead to a truncated or absent protein . Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria to be cla ssified as pathogenic (http://pcpgm.partners.org/LMM). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2018

Although the c.362delC pathogenic variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 121, changing it to an Arginine, and creating a premature stop codon at position 38 of the new reading frame, denoted p.Pro121ArgfsX38. This pathogenic 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 Human Gene Mutation Database in association with hypertrophic cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.362delC variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, c.362delC in the MYBPC3 gene is interpreted as a pathogenic variant. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2023

The c.362delC pathogenic mutation, located in coding exon 3 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 362, causing a translational frameshift with a predicted alternate stop codon (p.P121Rfs*38). THis alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Ho CY et al. Circulation, 2018 Oct;138:1387-1398). This variant is also 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

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: rs397516032; hg19: chr11-47372096;