rs727503203

chr11-47342928-AGG-Achr11-47342928-AGG-AGGG

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.1357_1358del(p.Pro453CysfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.51

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 11-47342928-AGG-A is Pathogenic according to our data. Variant chr11-47342928-AGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 164118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342928-AGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1357_1358del	p.Pro453CysfsTer21	frameshift_variant	16/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1357_1358del	p.Pro453CysfsTer21	frameshift_variant	16/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1357_1358del	p.Pro453CysfsTer21	frameshift_variant	15/34	5		A2
MYBPC3	ENST00000544791.1	c.1357_1358del	p.Pro453CysfsTer21	frameshift_variant, NMD_transcript_variant	16/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243790 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459270 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 725700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2019	PVS1, PM2, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2023	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; Reported in association with HCM (Waldmller et al., 2003; Walsh et al., 2017; Norrish et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31006259, 19574547, 27532257, 30731207, 12788380) -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change creates a premature translational stop signal (p.Pro453Cysfs*21) 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 present in population databases (rs727503203, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 12788380, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164118). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 05, 2013	proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 15, 2023

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000164118 / PMID: 12788380). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2020

The c.1357_1358delCC pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of two nucleotides at positions 1357 to 1358, causing a translational frameshift with a predicted alternate stop codon (p.P453Cfs*21). In a hypertrophic cardiomyopathy (HCM) cohort, this alteration was previously described in two Indian families, who were distantly related by a common founder and exhibited variable expressivity and incomplete penetrance (Waldmüller S et al. J Mol Cell Cardiol. 2003;35:623-36). This alteration has also been reported in association with dilated cardiomyopathy (DCM) Daoud H et al. J Mol Diagn, 2019 05;21:437-448). 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: rs727503203; hg19: chr11-47364479;