chr11-47342611-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 Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPS3PM2PP3_ModeratePP5_Strong

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 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: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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).; SCV004842467: In heart tissue engineered from mouse cardiac cells, this variant in heterozygous state was associated with a hypercontractile phenotype (PMID: 27108529).; SCV000208365: Functional studies examining the effect of c.1591 G>C in mouse-derived engineered heart tissue demonstrated that tissue expressing the variant is associated with a hypercontractile phenotype compared to wild type cardiac tissue (PMID: 27108529); SCV001356457: In heart tissue engineered from mouse cardiac cells, this variant in heterozygous state was associated with a hypercontractile phenotype (PMID: 27108529).; SCV002556034: At least one publication reports experimental evidence evaluating an impact on protein function, via measuring contraction forces in an engineered heart tissue assay from MYBPC3-knock out mice. Human wild-type and variant MYBPC3 was transduced into the engineered heart tissue and contraction was assayed at varying Ca2+ levels. The variant failed to rescue the hypercontractile phenotype seen in non-transduced (MYBPC3 null) samples, when expressed either alone or jointly with wild-type MYBPC3, demonstrating the variant may also act in a dominant-negative manner (Wijnker_2016).; SCV001156330: In vitro functional studies show that p.Gly531Arg causes hypercontractility in engineered heart tissue (Wijnker PJ, et al., 2016).; SCV002769189: "This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into knockout engineered heart cells mice tissues and expressed either as heterozygous or homozygous demonstrated abnormal force and contraction velocity compared to WT (PMID: 27108529)."; SCV002705733: "In a functional study utilizing engineered heart tissue derived from MYBPC3 knockout cardiomyocytes, c.1591G>C p.G531R was unable to completely rescue the hypercontractile phenotype of the knockout tissue; however, the physiological relevance of this result is unclear" (Wijnker PJ et al. J. Mol. Cell. Cardiol. 2016;97:82-92).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000013 — very rare for AD+AR gene (base 0.0001, raised to 0.000144 by highest known P/LP ClinVar AF 0.000144) — PM2 moderate.
	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).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (20/20 total P/LP).

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