rs730880685

chr11-47346638-GAA-G

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.913_914del(p.Phe305ProfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,367,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 2.20

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 11-47346638-GAA-G is Pathogenic according to our data. Variant chr11-47346638-GAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346638-GAA-G is described in Lovd as [Pathogenic]. Variant chr11-47346638-GAA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.913_914del	p.Phe305ProfsTer27	frameshift_variant	11/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.913_914del	p.Phe305ProfsTer27	frameshift_variant	11/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.913_914del	p.Phe305ProfsTer27	frameshift_variant	10/34	5		A2
MYBPC3	ENST00000544791.1	c.913_914del	p.Phe305ProfsTer27	frameshift_variant, NMD_transcript_variant	11/27	5

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150494 Hom.: 0 Cov.: 31

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000164 AC: 2 AN: 1217482 Hom.: 0 AF XY: 0.00000327 AC XY: 2 AN XY: 610872

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: 0.00000221

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150494 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73440

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: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	research	Rampazzo Lab, Human Molecular Genetics Unit, University of Padua	Apr 18, 2017	It is not found in 250 ethnically matched healthy controls (500 chromosomes), in dbSNP , in the 1000 Genomes Project database, in the Exome Variant Server or in the Exome Aggregation Consortium. We identified this mutation in 19 (19.5%) italian HCM patients (14 men and 5 women). Among 79 relatives belonging to 14 families, 45 resulted to be mutation carriers and 29 of them had phenotypical expression of HCM. A shared haplotype was found in all probands carrying the mutation, indicating that a common founder was likely in these families. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2023	The p.Phe305ProfsX27 in MYBPC3 has been reported in >20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with >10 affected relatives from >10 families (Olivotto 2008 PMID: 18533079, Millat 2010 PMID: 20800588, Marsiglia 2013 PMID: 24093860, Calore 2015 PMID: 25740977, LMM Data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42801). It has been identified in 0.002% (1/67564) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 305 and leads to a premature termination codon 27 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 autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change creates a premature translational stop signal (p.Phe305Profs*27) 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 (PMID: 18533079, 25740977, 27532257, 28794111). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42801). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jan 20, 2017	The MYBPC3 Phe305Profs*27 has been previously reported in mulitple HCM patients (Calore C, et al., 2015; Marsiglia JD, et al., 2013; Teirlinck CH, et al., 2012; Millat G, et al., 2010, Olivotto I, et al., 2008), and is an established Italian founder (Calore C, et al., 2015). This variant has not identified in the 1000 genomes project (http://www.1000genomes.org/), or in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Our lab has identified this variant in 2 HCM probands both of which are of Italian descent. 1 proband harbours a second variant (CRYAB 324+5G>T). Familial screening did not reveal a family history of disease or SCD, therefore the significance of the second variant (CRYAB 324+5G>T) is undetermined. Loss of function mutations in MYBPC3 are an established cause of HCM. Therefore, we classify MYBPC3 Phe305Profs*27 as "pathogenic". -

Hypertrophic cardiomyopathy 4 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 21, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jan 24, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	Not observed 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 in ClinVar as likely pathogenic/pathogenic by other clinical laboratories (ClinVar ID#42801; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25740977, 18533079, 20800588, 27532257, 28794111, 31513939, 28699631, 33673806) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2022	Variant summary: MYBPC3 c.913_914delTT (p.Phe305ProfsX27) 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 233482 control chromosomes (gnomAD). c.913_914delTT has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Calore_2015, Cecconi_2016, De Bortoli_2017). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 30, 2021	- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 14, 2015

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The c.913_914delTT pathogenic mutation, located in coding exon 11 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 913 to 914, causing a translational frameshift with a predicted alternate stop codon (p.F305Pfs*27). This variant has been detected in several individuals from hypertrophic cardiomyopathy cohorts, has shown segregation with disease in families, and has also been reported as an Italian founder mutation (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Marsiglia JD. Am. Heart J. 2013 Oct;166(4):775-82; Calore C et al. J. Med. Genet., 2015 May;52:338-47; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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. -

MYBPC3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2023

The MYBPC3 c.913_914delTT variant is predicted to result in a frameshift and premature protein termination (p.Phe305Profs*27). This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Olivotto et al. 2008. PubMed ID: 18533079; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S1, Robyns et al. 2020. PubMed ID: 31513939), and was considered an Italian founder variant (Calore et al. 2015. PubMed ID: 25740977). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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: rs397516080; hg19: chr11-47368189;