rs727503166

Variant names:

• chr11-47332109-CT-C
• rs727503166
• NM_000256.3:c.3776delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3776delA​(p.Gln1259ArgfsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,086 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. Q1259Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 1.03
• Publications: 12 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 11-47332109-CT-C is Pathogenic according to our data. Variant chr11-47332109-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3776delA	p.Gln1259ArgfsTer72	frameshift_variant	Exon 33 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3776delA	p.Gln1259ArgfsTer72	frameshift_variant	Exon 33 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3776delA	p.Gln1259ArgfsTer72	frameshift_variant	Exon 32 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248718 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111710

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 19808356, 19666645, 23674513, 20019025, 25611685, 27532257, 29121657, 30847666, 33662488); Identified in an infant with LVNC who also harbored a de novo missense variant in the MYBPC3 gene; the c.3776delA variant was subsequently identified in the infant's mildly affected mother (PMID: 20031619); Reported as a common pathogenic variant among individuals of Dutch background (PMID: 33662488); Frameshift variant predicted to result in protein truncation, as the last 16 amino acids are replaced with 71 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20019025, 22115648, 25611685, 27532257, 19666645, 29121657, 33532905, 33500567, 19808356, 30297972, 30847666, 27535533, 33662488, 37652022, 23674513, 20031619) -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 23674513,25611685) or Left ventricular noncompaction (PMID 20031619) and is extremely rare in general population databases. Therefore, this c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is classified as pathogenic. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1

Mar 22, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy;C1960469:Left ventricular noncompaction Pathogenic:1

Sep 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln1259fs variant in MYBPC3 has not been reported in the literature, but has been identified in 3 families with cardiomyopathy tested by our laboratory (Del lefave 2009, LMM unpublished data). In one family, an infant with LVNC and DCM ( likely to be burnt-out HCM) also carried a de novo variant in MYH7, while the af fected mother (LVNC) carried this frameshift variant in isolation (Dellefave 200 9). In a second family, this frameshift variant was observed in isolation in ind ividuals with HCM, though some individuals carried a second likely disease-causi ng variant in MYH7 causing a spectrum of cardiomyopathies to be observed in the family (including HCM, DCM, LVNC, and ARVC; LMM unpublished data). This frameshi ft variant is predicted to alter the protein?s amino acid sequence beginning at position 1259 and lead to a premature termination codon 72 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the MYBPC3 gene is an established disease mechan ism in HCM patients. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) -

Hypertrophic cardiomyopathy Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1259Argfs*72) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs727503166, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with left ventricular noncompaction or hypertrophic cardiomyopathy (PMID: 19808356, 20019025, 20031619, 22115648, 25611685, 27532257, 29121657). ClinVar contains an entry for this variant (Variation ID: 164021). This variant disrupts a region of the MYBPC3 protein in which other variant(s) (p.Arg1271*) have been determined to be pathogenic (PMID: 18533079, 23396983, 27532257). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3776delA pathogenic mutation, located in coding exon 33 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3776. This deletion causes a translational frameshift that ablates the C-terminal 16 amino acids and replaces them with 72 spurious amino acids, resulting in an elongated protein with an altered C-terminal domain (p.Q1259Rfs*72). This alteration was described in a proband with left ventricular non-compaction cardiomyopathy, who also had a de novo missense alteration in the second allele. The proband was reported to have no normal MYBPC3 protein expression and disorganized sarcomere M bands. This alteration was also present in the proband's mildly affected mother who was 28 years old at the time of examination (Dellefave LM et al. Circ Cardiovasc Genet. 2009;2:442-9). In another study, this alteration was detected in an individual with hypertrophic cardiomyopathy and two unaffected family members (Michels M et al. Eur Heart J. 2009;30:2593-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503166; hg19: chr11-47353660;