11-47346320-C-A

Variant names:

• chr11-47346320-C-A
• rs34580776
• NM_000256.3:c.977G>T
• MYBPC3 p.Arg326Leu

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 (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Moderate

The NM_000256.3(MYBPC3):c.977G>T (p.Arg326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000225, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R326Q: Benign/Likely_benign (ClinVar VariationId 42813, 2 stars); p.R326= (synonymous): Likely_benign (ClinVar VariationId 1535531, 1 star); p.R326W: Uncertain_significance (ClinVar VariationId 525027, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 23 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 ACMG Germline Pathogenicity v2019

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
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000225 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000144 by highest known P/LP ClinVar AF 0.000144) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Arg326Leu	missense	Exon 12 of 35	Prot: NP_000247.2 UniProt:

MYBPC3 NM_000256.3

MANE Select

HGVSc / HGVSpc.977G>Tp.Arg326Leu

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>T p.Arg326Leu	missense	Exon 12 of 35	Prot: ENSP00000442795.1 UniProt:
	MYBPC3 ENST00000399249.6	TSL:5	c.977G>T p.Arg326Leu	missense	Exon 11 of 34	Prot: ENSP00000382193.2 UniProt:
	MYBPC3 ENST00000544791.1	TSL:5	n.977G>T	non_coding_transcript_exon	Exon 12 of 27	Prot: ENSP00000444259.1 UniProt:

MYBPC3 ENST00000545968.6

TSL:5MANE Select

HGVSc / HGVSpc.977G>Tp.Arg326Leu

Exon rankExon 12 of 35

missense

Prot: ENSP00000442795.1UniProt: Q14896-1

MYBPC3 ENST00000399249.6

TSL:5

HGVSc / HGVSpc.977G>Tp.Arg326Leu

Exon rankExon 11 of 34

missense

Prot: ENSP00000382193.2UniProt: A8MXZ9

MYBPC3 ENST00000544791.1

TSL:5

HGVSc / HGVSpn.977G>T

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 6.85e-7	AC:1	Hom:0	AN:1459334	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
CardioboostCm	Benign	0.052
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.066
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Benign	0.20
GPN-Star LLR	N/A	-8.0
GPN-Star score	N/A	8.0
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.89	T
Mutation Taster	N/A	63/37	polymorphism
MutationAssessor	Benign	1.3	L
PhyloP100	Benign	1.2
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.45
VESM-3B	Benign	-9.7

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.11	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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar