rs397515947

Positions:

• chr11-47339375-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2096del​(p.Pro699GlnfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,686 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: 0.0000062 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.537

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47339375-TG-T is Pathogenic according to our data. Variant chr11-47339375-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 42596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47339375-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2096del	p.Pro699GlnfsTer55	frameshift_variant	22/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2096del	p.Pro699GlnfsTer55	frameshift_variant	22/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2096del	p.Pro699GlnfsTer55	frameshift_variant	21/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.2096del	p.Pro699GlnfsTer55	frameshift_variant, NMD_transcript_variant	22/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727132

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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 as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 42596; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15114369, 25351510, 9562578, 24793961, 15519027, 22122802, 26743238, 26914223, 27532257, 28615295, 31006259, 23549607, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2021	PVS1, PM2, PS4_moderate, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 13, 2018	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2023	This variant deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), 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 over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). 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. -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 28, 2017	The p.Pro699fs variant (also referred to as Ala698fs and A698fs54) in MYBPC3 has been reported in 8 individuals with HCM and segregated with disease in 5 affect ed family members (Nimura 1998, Van Driest 2004, Wilson 2011, Bos 2014, LMM data ). It has not been identified in large population studies. This variant is predi cted to cause a frameshift, which alters the protein?s amino acid sequence begin ning at position 699 and leads to a premature termination codon 55 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic b ased upon segregation studies, absence from controls, and the predicted impact t o the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change creates a premature translational stop signal (p.Pro699Glnfs*55) 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 individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 15519027, 22122802, 24793961, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as delC698 and A698fs/54. ClinVar contains an entry for this variant (Variation ID: 42596). For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Aug 01, 2017

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Mar 15, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

The c.2096delC pathogenic mutation, located in coding exon 22 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2096, causing a translational frameshift with a predicted alternate stop codon (p.P699Qfs*55). This mutation has been reported in multiple individuals and families with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Wilson MG et al. J Cardiovasc Magn Reson, 2011 Nov;13:77; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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: rs397515947; hg19: chr11-47360926;