11-47342611-C-G

Variant names:

• chr11-47342611-C-G
• rs397515912
• NM_000256.3:c.1591G>C
• MYBPC3 p.Gly531Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO6_SupportingO7_Supporting

The NM_000256.3(MYBPC3):c.1591G>C (p.Gly531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000192 (AC=31) in the gnomAD database across 1,612,456 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000013. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.50). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000059064: A functional study in which the c.1591G>C (p.Gly531Arg) variant was transfected into MYBPC3 knockout mouse cardiomyocytes alone and in combination with wild-type MYBPC3 (to represent homozygous and heterozygous disease states) revealed abnormal contractile force in both scenarios compared to wild-type (Wijnker 2016 PMID:27108529)." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G531= (synonymous): Likely_benign (ClinVar VariationId 1603907, 1 star); p.G531= (synonymous): Likely_benign (ClinVar VariationId 164108, 2 stars); p.G531W: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 810736)

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.50
• Publications: 8 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 3 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 = 0.000013 — very rare (O3 supporting [+1])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 1 pathogenic, 0 benign (OR vs. background: 15.0); Variant does not impact splicing — splice-hotspot path not applicable

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.1591G>C p.Gly531Arg	missense	Exon 17 of 35	Prot: NP_000247.2 UniProt:

MYBPC3 NM_000256.3

MANE Select

HGVSc / HGVSpc.1591G>Cp.Gly531Arg

Exon rankExon 17 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.1591G>C p.Gly531Arg	missense	Exon 17 of 35	Prot: ENSP00000442795.1 UniProt:
	MYBPC3 ENST00000399249.6	TSL:5	c.1591G>C p.Gly531Arg	missense	Exon 16 of 34	Prot: ENSP00000382193.2 UniProt:
	MYBPC3 ENST00000544791.1	TSL:5	n.1591G>C	non_coding_transcript_exon	Exon 17 of 27	Prot: ENSP00000444259.1 UniProt:

MYBPC3 ENST00000545968.6

TSL:5MANE Select

HGVSc / HGVSpc.1591G>Cp.Gly531Arg

Exon rankExon 17 of 35

missense

Prot: ENSP00000442795.1UniProt: Q14896-1

MYBPC3 ENST00000399249.6

TSL:5

HGVSc / HGVSpc.1591G>Cp.Gly531Arg

Exon rankExon 16 of 34

missense

Prot: ENSP00000382193.2UniProt: A8MXZ9

MYBPC3 ENST00000544791.1

TSL:5

HGVSc / HGVSpn.1591G>C

Exon rankExon 17 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: 0.0000197	AC:3	Hom:0	AN:152208	Cov:33
GnomAD2 exomes	AF: 0.0000121	AC:3	Hom:	AN:247086	Cov:
GnomAD4 exome	AF: 0.0000185	AC:27	Hom:0	AN:1460130	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152326	Cov:33
TOPMed (Bravo)	AF: 0.0000189	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000111	AC:1	Hom:0	AN:90460	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000355	AC:2	Hom:0	AN:5158	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28400	0.0000347	1	28828
Epi25(Epilepsy)	0.0000238	1	41950	0.0000150	1	66812
SCHEMA(Schizophrenia)	0.00	0	112988	0.0000105	2	189958

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Hypertrophic cardiomyopathy 4 (7)
4	-	-	Hypertrophic cardiomyopathy (4)
3	-	-	not provided (3)
2	-	-	Cardiomyopathy (2)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
CardioboostCm	Uncertain	0.38
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-4.8
GPN-Star score	N/A	4.8
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.53	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.5	M
PhyloP100	Uncertain	7.5
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.61
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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: rs397515912;

hg19: chr11-47364162;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar