rs397515925

chr11-47351343-CGTGTGCCCTCT-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.177_187del(p.Glu60AlafsTer49) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000025 in 1,600,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T59T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.72

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 11-47351343-CGTGTGCCCTCT-C is Pathogenic according to our data. Variant chr11-47351343-CGTGTGCCCTCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47351343-CGTGTGCCCTCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.177_187del	p.Glu60AlafsTer49	frameshift_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.177_187del	p.Glu60AlafsTer49	frameshift_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.177_187del	p.Glu60AlafsTer49	frameshift_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.177_187del	p.Glu60AlafsTer49	frameshift_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152264 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447746 Hom.: 0 AF XY: 0.00000278 AC XY: 2 AN XY: 718872

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74398

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

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	Feb 01, 2019	The p.Glu60AlafsX49 variant in MYBPC3 has been reported in 9 individuals with HCM (7 individuals: Zimmerman 2010, Alfares 2015, Walsh 2016; 1 individual: Burns 2016; 1 individual: Murphy 2017) and segregated with disease in 1 affected (LMM data). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42565). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 60 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Glu60Alafs*49) 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 individual(s) with dilated cardiomyopathy (PMID: 20474083). ClinVar contains an entry for this variant (Variation ID: 42565). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jul 01, 2015	MYBPC3 Glu60Alafs*49 has been observed previously >10 probands with HCM (Walsh et al., 2017; Kapplinger et al., 2014) and has also been reported in a DCM case (Zimmerman et al, 2010). It is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this MYBPC3 Glu60Alafs*49 in a HCM proband and the variant was found to segregate to two affected family members (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been seen reported in more than 10 unrelated HCM probands (PS4) and is rare in the general population (PM2), therefore we classify MYBPC3 Glu60Alafs*49 as "Pathogenic". -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2019	This variant deletes 11 nucleotides in exon 2 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 23690394, 24510615, 25543971, 25611685, 26914223, 27532257). 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. Based on the available evidence, this variant is classified as Pathogenic. -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Heart Center, Academic Medical Center Amsterdam

Dec 01, 2018

- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Sep 06, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2022

Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation and nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20474083, 25228707, 25611685, 26914223, 27532257, 28790153, 23690394, 24510615, 21943931, 21415409, 25543971) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Feb 21, 2019

The c.177_187del (p.Glu60Alafs*49) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals affected with HCM, DCM or ARVC (PMID 20474083, 24510615, 25611685, 26914223,27532257) and has never been reported in general population databases. Therefore, this c.177_187del (p.Glu60Alafs*49) variant in the MYBPC3 gene is classified as pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 05, 2022

Variant summary: MYBPC3 c.177_187del11 (p.Glu60AlafsX49) 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 226260 control chromosomes. c.177_187del11 has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

The c.177_187del11 pathogenic mutation, located in coding exon 2 of the MYBPC3 gene, results from a deletion of 11 nucleotides at nucleotide positions 177 to 187, causing a translational frameshift with a predicted alternate stop codon (p.E60Afs*49). This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J Am Coll Cardiol, 2004 Nov;44:1903-10; Zimmerman RS et al. Genet Med, 2010 May;12:268-78; Valente AM et al. Circ Cardiovasc Genet, 2013 Jun;6:230-7; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Ho CY et al. JACC Heart Fail, 2015 Feb;3:180-8; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 02;19:192-203; Lahrouchi N et al. Eur J Hum Genet, 2020 01;28:17-22). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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: rs397515925; hg19: chr11-47372894;