NM_000256.3:c.977G>A

Variant names:

• chr11-47346320-C-T
• rs34580776
• NM_000256.3:c.977G>A
• MYBPC3 p.Arg326Gln

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-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). B3_Supporting

The NM_000256.3(MYBPC3):c.977G>A (p.Arg326Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.003 (AC=4,842) in the gnomAD database across 1,611,640 control chromosomes, including 28 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00453. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R326= (synonymous): Likely_benign (ClinVar VariationId 1535531, 1 star); p.R326W: Uncertain_significance (ClinVar VariationId 525027, 2 stars) The variant has been observed in cBioPortal in 3 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). 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 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (27 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 1.16
• Publications: 36 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: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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.977G>A p.Arg326Gln	missense	Exon 12 of 35	Prot: NP_000247.2 UniProt:

MYBPC3 NM_000256.3

MANE Select

HGVSc / HGVSpc.977G>Ap.Arg326Gln

Exon rankExon 12 of 35

missense

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.977G>A p.Arg326Gln	missense	Exon 12 of 35	Prot: ENSP00000442795.1 UniProt:
	MYBPC3 ENST00000399249.6	TSL:5	c.977G>A p.Arg326Gln	missense	Exon 11 of 34	Prot: ENSP00000382193.2 UniProt:
	MYBPC3 ENST00000544791.1	TSL:5	n.977G>A	non_coding_transcript_exon	Exon 12 of 27	Prot: ENSP00000444259.1 UniProt:

MYBPC3 ENST00000545968.6

TSL:5MANE Select

HGVSc / HGVSpc.977G>Ap.Arg326Gln

Exon rankExon 12 of 35

missense

Prot: ENSP00000442795.1UniProt: Q14896-1

MYBPC3 ENST00000399249.6

TSL:5

HGVSc / HGVSpc.977G>Ap.Arg326Gln

Exon rankExon 11 of 34

missense

Prot: ENSP00000382193.2UniProt: A8MXZ9

MYBPC3 ENST00000544791.1

TSL:5

HGVSc / HGVSpn.977G>A

Exon rankExon 12 of 27

non_coding_transcript_exon

Prot: ENSP00000444259.1UniProt: F5GZR4

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: 0.00348	AC:530	Hom:1	AN:152196	Cov:32
GnomAD2 exomes	AF: 0.00406	AC:991	Hom:	AN:243898	Cov:
GnomAD4 exome	AF: 0.00295	AC:4312	Hom:27	AN:1459328	Cov:32
GnomAD4 genome	AF: 0.00348	AC:530	Hom:1	AN:152312	Cov:32
TOPMed (Bravo)	AF: 0.00197	AC:521	Hom:3	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00378	AC:381	Hom:5	AN:100708	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00171	AC:4	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00249	AC:32	Hom:	AN:12852	Cov:
Qatari Genome	AF: 0.0114	AC:2	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122496	Cov:
Turkish Variome	AF: 0.00567	AC:38	Hom:0	AN:6702	Cov:
UK10K	AF: 0.000926	AC:7	Hom:	AN:7562	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00923 *	13	1408	0.00750 *	53	7062
BipEx(Bipolar disorder (including schizoaffective))	0.00415	118	28416	0.00420	121	28838
Epi25(Epilepsy)	0.00472	198	41958	0.00292	195	66854
SCHEMA(Schizophrenia)	0.00300	339	113008	0.00330	627	190258

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Hypertrophic cardiomyopathy (5)
-	-	5	Hypertrophic cardiomyopathy 4 (5)
-	-	4	not provided (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1A (1)
-	-	1	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
-	-	1	Left ventricular noncompaction 10 (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Primary dilated cardiomyopathy;C0151636:Premature ventricular contraction (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.89	D
GPN-Star LLR	N/A	-5.7
GPN-Star score	N/A	5.7
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.78	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Uncertain	2.2	M
PhyloP100	Benign	1.2
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.078
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.048	D
Varity_R	N/A	0.16
VESM-3B	Benign	-7.7

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.070	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: rs34580776;

hg19: chr11-47367871;

COSMIC: COSV57033344;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar