rs730880657

Positions:

• chr11-47335894-TCCACGCTGTAG-T

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.2709_2719del​(p.Tyr904ValfsTer143) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,832 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: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.92

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 11-47335894-TCCACGCTGTAG-T is Pathogenic according to our data. Variant chr11-47335894-TCCACGCTGTAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 181084.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.2709_2719del	p.Tyr904ValfsTer143	frameshift_variant	26/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2709_2719del	p.Tyr904ValfsTer143	frameshift_variant	26/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2709_2719del	p.Tyr904ValfsTer143	frameshift_variant	25/34	5		A2
MYBPC3	ENST00000544791.1	c.*214_*224del		3_prime_UTR_variant, NMD_transcript_variant	26/27	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380832 Hom.: 0 AF XY: 0.00000147 AC XY: 1 AN XY: 680340

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2021	Reported in one patient in the eMERGE III cohort (eMERGE Consortium, 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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 ClinVar as pathogenic (ClinVar Variant ID# 181084; ClinVar); This variant is associated with the following publications: (PMID: 31447099, 26582918) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	The MYBPC3 c.2709_2719del; p.Tyr904fs variant (rs730880657), to our knowledge, is not reported in the medical literature but is reported as pathogenic in ClinVar (Variation ID: 181084). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 11 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function of MYBPC3 is an established mechanism of disease and downstream truncating variants are reported in individuals with hypertrophic cardiomyopathy (Waldmuller 2011, Zou 2013). Based on available information, the c.2709_2719del variant is considered to be pathogenic. References: Waldmuller S et al. Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. Eur J Heart Fail. 2011;13(11):1185-1192. Zou Y et al. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep. 2013;40(6):3969-3976. -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 181084). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr904Valfs*143) 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	Apr 13, 2021	The p.Tyr904ValfsX143 variant in MYBPC3 has been identified by our laboratory in two individuals with HCM, and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 181084). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 904 and leads to a premature termination codon 143 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.2709_2719del11 pathogenic mutation, located in coding exon 26 of the MYBPC3 gene, results from a deletion of 11 nucleotides at nucleotide positions 2709 to 2719, causing a translational frameshift with a predicted alternate stop codon (p.Y904Vfs*143). 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: rs730880657; hg19: chr11-47357445;