chr11-47335120-G-A

Variant names:

• chr11-47335120-G-A
• rs387907267
• NM_000256.3:c.2827C>T
• MYBPC3 p.Arg943*

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_000256.3(MYBPC3):c.2827C>T (p.Arg943*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000013 (AC=21) in the gnomAD database across 1,612,276 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000459. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005399406: "This variant has moderate functional evidence supporting abnormal protein function. Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) heterozygous for this variant demonstrated aberrant calcium signalling and prolonged relaxation kinetics compared to WT cells, with homozygous iPSC-CMs demonstrating more severe impairment (PMID:30586709)."" and additional evidence is available in ClinVar. The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 6.30
• Publications: 68 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• left ventricular noncompaction 10

  Inheritance: AD, AR 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, G2P
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD, AR Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000046 — very rare (O3 supporting [+1])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYBPC3 NM_000256.3	MANE Select	c.2827C>T p.Arg943*	stop_gained	Exon 27 of 35	Prot: NP_000247.2 UniProt:

MYBPC3 NM_000256.3

MANE Select

HGVSc / HGVSpc.2827C>Tp.Arg943*

Exon rankExon 27 of 35

stop_gained

Prot: NP_000247.2UniProt: Q14896-1A5YM48

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MYBPC3 ENST00000545968.6	TSL:5MANE Select	c.2827C>T p.Arg943*	stop_gained	Exon 27 of 35	Prot: ENSP00000442795.1 UniProt:
	MYBPC3 ENST00000399249.6	TSL:5	c.2827C>T p.Arg943*	stop_gained	Exon 26 of 34	Prot: ENSP00000382193.2 UniProt:

MYBPC3 ENST00000545968.6

TSL:5MANE Select

HGVSc / HGVSpc.2827C>Tp.Arg943*

Exon rankExon 27 of 35

stop_gained

Prot: ENSP00000442795.1UniProt: Q14896-1

MYBPC3 ENST00000399249.6

TSL:5

HGVSc / HGVSpc.2827C>Tp.Arg943*

Exon rankExon 26 of 34

stop_gained

Prot: ENSP00000382193.2UniProt: A8MXZ9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152170	Cov:33
GnomAD2 exomes	AF: 0.0000121	AC:3	Hom:	AN:247124	Cov:
GnomAD4 exome	AF: 0.0000116	AC:17	Hom:0	AN:1460106	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152170	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000155	AC:28	Hom:0	AN:180886	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122146	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000353	1	28324	0.00	0	28750
SCHEMA(Schizophrenia)	0.0000266	3	112834	0.0000158	3	189992

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Hypertrophic cardiomyopathy 4 (9)
9	-	-	not provided (9)
6	-	-	Hypertrophic cardiomyopathy (6)
3	-	-	Cardiomyopathy (3)
1	-	-	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	40
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
GPN-Star LLR	N/A	-9.5
GPN-Star score	N/A	9.2
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	6.3

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs387907267;

hg19: chr11-47356671;

COSMIC: COSV57023485;

COSMIC: COSV57023485;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar