rs730880565

Variant names:

• chr11-47337722-G-A
• rs730880565
• NM_000256.3:c.2381C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000256.3(MYBPC3):​c.2381C>T​(p.Pro794Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000804 in 1,566,584 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P794T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000083 (1 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:6
• Conservation: PhyloP100: 6.54
• Publications: 7 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• BP6: Variant 11-47337722-G-A is Benign according to our data. Variant chr11-47337722-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180968.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2381C>T	p.Pro794Leu	missense_variant	Exon 24 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2381C>T	p.Pro794Leu	missense_variant	Exon 24 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2381C>T	p.Pro794Leu	missense_variant	Exon 23 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2381C>T		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 25 AN: 173856 AF XY: 0.000172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000834 AC: 118 AN: 1414508 Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 75 AN XY: 699368

African (AFR) AF: 0.0000310 AC: 1 AN: 32214

American (AMR) AF: 0.0000535 AC: 2 AN: 37384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 36850

South Asian (SAS) AF: 0.000990 AC: 80 AN: 80826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49866

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5710

European-Non Finnish (NFE) AF: 0.0000221 AC: 24 AN: 1087684

Other (OTH) AF: 0.000153 AC: 9 AN: 58652

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000938 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Nov 01, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Pro794Leu (c.2381C>T) in exon 24 of the MYBPC3 gene (NM_000256.3; chr11-47359273-G-A) SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and lack of segregation data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYBPC3: Pathogenic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). However, there are several missense variants in MYBPC3 known to cause disease. MYBPC3 encodes cardiac myosin-binding protein C. It binds myosin heavy chain and titin. Phosphorylation of MYBPC3 modulates contraction of the sarcomere. Region level data: Amr et al 2016: patients with HCM with variants in this region are overrepresented compared to controls. Case data (not including our patient): at least 3 · ClinVar: § GeneDx (likely path), Laboratory for Molecular Medicine (VUS) and Blueprint Genetics (VUS): § LMM saw this variant in a whole exome/genome case but was not fully reviewed. § GeneDx saw this variant in one patient with HCM who had another pathogenic variant. However, neither of these variants have been reviewed since updated variant classification guidelines were published § Blueprint has downgraded their classification of this variant to VUS from likely path. · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The proline at codon 794 is not completely conserved across species. Nearby pathogenic variants at this codon or neighboring codons: A truncating variant at this codon, p.Pro794fs*26, is reported in 1 of ~400 patients with HCM (Van Driest et al 2004). Other truncating variants are nearby (p.Gln791Ter, p.Trp792Valfs, p.Trp792Ter, p.Pro795Leufs, p.Gly799Trpfs). A missense variant at a nearby codon is classified as pathogenic by multiple labs: p.Trp792Arg. Population data: Highest MAF in the South Asian population: 0.079%. The variant was reported online in 27 of 99,709 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 19 of 12,073 individuals of South Asian descent (MAF=0.079%), 1 of 2,571 individuals of "other" descent, 6 of 41,715 individuals of European descent and 1 of 13,128 individuals of Latino descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

May 07, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with cardiomyopathy and/or past history of sudden cardiac arrest (PMID: 28518168, 31110529, 32659924, 32841044, 36588553, 35653365, 37652022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 32659924, 27532257, 31110529, 35653365, 37652022, 36588553, 32841044, 28518168) -

Cardiovascular phenotype Uncertain:1 Benign:1

Aug 07, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Dec 09, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro794Leu variant in MYBPC3 is classified as likely benign because it has been identified in 0.08% (19/24078) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Apr 15, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.2381C>T (p.Pro794Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 1566584 control chromosomes in the gnomAD (v4.1) database, including 1 homozygote. c.2381C>T has been observed in individuals affected with Cardiomyopathy (e.g., McGurk_2023). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 180968). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Benign:2

Feb 20, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Mar 26, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Benign	0.024
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.0042	D
MutationAssessor	Pathogenic	3.4	M;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.78
MVP		0.92
MPC		0.83
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.51
gMVP		0.78
Mutation Taster		=79/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730880565; hg19: chr11-47359273;