NM_000256.3:c.2459G>C

Variant names:

• chr11-47337534-C-G
• rs2856655
• NM_000256.3:c.2459G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000256.3(MYBPC3):​c.2459G>C​(p.Arg820Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 3.87
• Publications: 29 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD 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
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337535-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195850.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 11-47337534-C-G is Pathogenic according to our data. Variant chr11-47337534-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180970.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2459G>C	p.Arg820Pro	missense_variant	Exon 25 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2459G>C	p.Arg820Pro	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2459G>C	p.Arg820Pro	missense_variant	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2414-23G>C		intron_variant	Intron 24 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:2

Aug 17, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM2,PM5 -

not specified Uncertain:1

May 19, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg820Pro variant in the MYBPC3 gene has also not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Arg820Pro results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Proline at a position that is conserved across species. In silico analysis predicts Arg820Pro is probably damaging to the protein structure/function. In addition, the NHLBI ESP Exome Variant Server reports Arg820Pro was not observed in approximately 4,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, a different non-conservative change at this position (Arg820Gln) has been reported with an allele frequency of 0.6-1.2% in individuals of various ethnic backgrounds (dbSNP: rs2856655), indicating this codon may tolerate change. In summary, the clinical significance of Arg820Pro in the MYBPC3 gene is currently unknown. Variants in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hypertrophic cardiomyopathy Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 820 of the MYBPC3 protein (p.Arg820Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 180970). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg820 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12628722, 12951062, 18929575, 25281569). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.026	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.92
MVP		0.90
MPC		1.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.92
gMVP		0.88
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2856655; hg19: chr11-47359085;