11-47342734-C-T

Variant names:

• chr11-47342734-C-T
• rs200625851
• NM_000256.3:c.1468G>A
• MYBPC3 p.Gly490Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM1PM5PP3_ModerateBS2

The NM_000256.3(MYBPC3):c.1468G>A (p.Gly490Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000343 (AC=553) in the gnomAD database across 1,613,830 control chromosomes, including 2 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.000377. 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: 7.51). Variant has been reported in ClinVar as Uncertain Significance (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G490V: Pathogenic (ClinVar VariationId 64617, 0 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G490E: Uncertain_significance (ClinVar VariationId 862072, 1 star); p.G490= (synonymous): Likely_benign (ClinVar VariationId 2034499, 1 star); p.G490R: Uncertain_significance (ClinVar VariationId 454304, 2 stars); p.G490W: Uncertain_significance (ClinVar VariationId 4768323, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:17 B:2
• Conservation: PhyloP100: 7.51
• Publications: 25 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 0 benign (OR vs. background: 55.0).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.G490V: Pathogenic (ClinVar VariationId 64617, 0 stars); Other variants at the same amino acid residue (not pathogenic): p.G490E: Uncertain_significance (ClinVar VariationId 862072, 1 star); p.G490= (synonymous): Likely_benign (ClinVar VariationId 2034499, 1 star); p.G490R: Uncertain_significance (ClinVar VariationId 454304, 2 stars); p.G490W: Uncertain_significance (ClinVar VariationId 4768323, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 2.; Very high cumulative gnomAD AC = 553 (any gene).

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.1468G>A p.Gly490Arg	missense	Exon 17 of 35	Prot: NP_000247.2 UniProt:

MYBPC3 NM_000256.3

MANE Select

HGVSc / HGVSpc.1468G>Ap.Gly490Arg

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.1468G>A p.Gly490Arg	missense	Exon 17 of 35	Prot: ENSP00000442795.1 UniProt:
	MYBPC3 ENST00000399249.6	TSL:5	c.1468G>A p.Gly490Arg	missense	Exon 16 of 34	Prot: ENSP00000382193.2 UniProt:
	MYBPC3 ENST00000544791.1	TSL:5	n.1468G>A	non_coding_transcript_exon	Exon 17 of 27	Prot: ENSP00000444259.1 UniProt:

MYBPC3 ENST00000545968.6

TSL:5MANE Select

HGVSc / HGVSpc.1468G>Ap.Gly490Arg

Exon rankExon 17 of 35

missense

Prot: ENSP00000442795.1UniProt: Q14896-1

MYBPC3 ENST00000399249.6

TSL:5

HGVSc / HGVSpc.1468G>Ap.Gly490Arg

Exon rankExon 16 of 34

missense

Prot: ENSP00000382193.2UniProt: A8MXZ9

MYBPC3 ENST00000544791.1

TSL:5

HGVSc / HGVSpn.1468G>A

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: 0.000223	AC:34	Hom:0	AN:152244	Cov:33
GnomAD2 exomes	AF: 0.000221	AC:55	Hom:	AN:249060	Cov:
GnomAD4 exome	AF: 0.000355	AC:519	Hom:2	AN:1461586	Cov:31
GnomAD4 genome	AF: 0.000223	AC:34	Hom:0	AN:152244	Cov:33
TOPMed (Bravo)	AF: 0.000185	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000343	AC:156	Hom:0	AN:454332	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000314	AC:4	Hom:	AN:12728	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5174	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000844 *	8	9480	0.00184 *	19	10324
BipEx(Bipolar disorder (including schizoaffective))	0.000317	9	28420	0.000416	12	28844
Epi25(Epilepsy)	0.000215	9	41958	0.000239	16	66886
SCHEMA(Schizophrenia)	0.000238	29	121704	0.000241	46	190498

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	3	-	Hypertrophic cardiomyopathy (3)
-	1	1	Cardiomyopathy (2)
-	2	-	Cardiovascular phenotype (2)
-	2	-	Left ventricular noncompaction 10 (2)
-	2	-	Primary familial hypertrophic cardiomyopathy (2)
1	-	-	Cardiomyopathy, dilated, 1MM (1)
1	-	-	Hypertrophic cardiomyopathy 4 (1)
-	1	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
-	1	-	MYBPC3-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
CardioboostCm	Uncertain	0.41
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.92
GPN-Star LLR	N/A	-5.6
GPN-Star score	N/A	5.6
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.83	D
Mutation Taster	N/A	2/98	disease causing
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Uncertain	7.5
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.79
VESM-3B	Benign	-9.4

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.10	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: rs200625851;

hg19: chr11-47364285;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar