rs775404728

Variant names:

• chr11-47337535-G-A
• rs775404728
• NM_000256.3:c.2458C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47337535-G-A
• chr11-47337535-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.2458C>T​(p.Arg820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,686 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. R820P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:2
• Conservation: PhyloP100: 1.47
• Publications: 27 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 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337534-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180970.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 11-47337535-G-A is Pathogenic according to our data. Variant chr11-47337535-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195850.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2458C>T	p.Arg820Trp	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.2458C>T	p.Arg820Trp	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2458C>T	p.Arg820Trp	missense_variant	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2414-24C>T		intron_variant	Intron 24 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249210 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461686 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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: 53388

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111864

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:4

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the homozygous state in two related individuals affected with hypertrophic cardiomyopathy and left ventricular non-compaction; however, heterozygous carriers in this family were unaffected [PMID: 20542340]. Experimental studies have shown that felines with an equivalent variant develop hypertrophic cardiomyopathy [PMID: 17521870], however the clinical significance of this observation is uncertain. Another missense substitution at the same codon (p.Arg820Gln) has been reported as pathogenic [PMID: 12628722, 22112859, 22267749]. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:2

Dec 04, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar (ClinVar Variant ID# 195850; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30284024, 19566849, 26776581, 28868097, 21147473, 26776585, 25622655, 26776584, 27076529, 26776595, 24602043, 21051304, 24906243, 23323744, 17521870, 21415409, 24447051, 29907873, 19035361, 29636697, 28642712, 28679633, 28771489, 20542340) -

May 04, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:2

Nov 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 820 in the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using a transgenic Drosophila model showed that this variant produced a phenotype consistent with hypertrophic cardiomyopathy (PMID: 33561224). This variant has been observed in both heterozygous and homozygous state in ragdoll cats affected with hypertrophic cardiomyopathy (PMID: 17521870); the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in at least 8 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 28771489, 33407484, 33782553, 34310159; ClinVar SCV000546424.8, SCV002738183.1). It has also been reported in the homozygous state in 2 individuals from one family affected with hypertrophic cardiomyopathy (PMID: 20542340) and in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 33386538). A different variant occurring at the same codon, p.Arg820Gln, is considered to be disease-causing (Clinvar variation ID: 8617), suggesting that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 1/249210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 03, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 820 of the MYBPC3 protein (p.Arg820Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 20542340, 28771489, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 195850). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 17521870, 24906243, 26776584). 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, 22112859, 22267749, 25281569). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Nov 21, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R820W variant (also known as c.2458C>T), located in coding exon 25 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2458. The arginine at codon 820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the heterozygous and homozygous states in individuals with hypertrophic cardiomyopathy (HCM); however, heterozygous relatives of the homozygous proband were reportedly unaffected (Ripoll Vera T et al, Int. J. Cardiol. 2010 Nov; 145(2):405-7; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Chung H et al. Cardiovasc Ultrasound, 2021 Jan;19:4; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799; Ambry internal data). The same alteration (p.R820W) has also been detected in ragdoll cats exhibiting HCM (Meurs KM et al. Genomics, 2007 Aug;90:261-4). Another alteration at the same codon, p.R820Q (c.2459G>A), has been detected in individuals with HCM (Konno T et al. J. Am. Coll. Cardiol., 2003 Mar;41:781-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
CardioboostCm	Uncertain	0.90
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Pathogenic	3.7	H;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.5	D;.;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.95
MVP		0.86
MPC		0.85
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.72
gMVP		0.75
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs775404728; hg19: chr11-47359086;