rs397516023

chr11-47350557-AG-A

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.350del(p.Pro117LeufsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,938 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: 7.2e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.11

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 11-47350557-AG-A is Pathogenic according to our data. Variant chr11-47350557-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 42718.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.350del	p.Pro117LeufsTer42	frameshift_variant	3/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.350del	p.Pro117LeufsTer42	frameshift_variant	3/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.350del	p.Pro117LeufsTer42	frameshift_variant	3/34	5		A2
MYBPC3	ENST00000544791.1	c.350del	p.Pro117LeufsTer42	frameshift_variant, NMD_transcript_variant	3/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393938 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690666

Gnomad4 AFR exome AF: 0.0000333

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2011	The Pro117fs variant has not been previously reported nor previously identified by our laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 117 and leads to a prematu re stop codon 42 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Loss of function is an established mechan ism of disease for the MYBPC3 gene, which makes it highly likely that the Pro117 fs variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This variant deletes 1 nucleotide in exon 3 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 28241245, 28611029, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2023	This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28611029). This sequence change creates a premature translational stop signal (p.Pro117Leufs*42) 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). ClinVar contains an entry for this variant (Variation ID: 42718). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2022

Variant summary: MYBPC3 c.350delC (p.Pro117LeufsX42) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 155646 control chromosomes (gnomAD). c.350delC has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Ho_2018, Haskell_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2017

Although the c.350delC pathogenic variant in the MYBPC3 gene has not been reported to our knowledge, it has been classified as pathogenic by another clinical laboratory in ClinVar (SCV000059244.4; Landrum et al., 2016). The c.350delC variant causes a shift in reading frame starting at codon proline 117, changing it to a leucine, and creating a premature stop codon at position 42 of the new reading frame, denoted p.Pro117LeufsX42. 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 cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.350delC variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2020

The c.350delC pathogenic mutation, located in coding exon 3 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 350, causing a translational frameshift with a predicted alternate stop codon (p.P117Lfs*42). This mutation has been reported in one individual with hypertrophic cardiomyopathy from an exome testing cohort (Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]). 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: rs397516023; hg19: chr11-47372108;