chr11-47341207-C-T

Variant names:

• chr11-47341207-C-T
• rs371564200
• NM_000256.3:c.1828G>A

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.1828G>A​(p.Asp610Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,598,984 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. D610H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:11
• Conservation: PhyloP100: 7.48
• Publications: 14 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47341207-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42576.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 11-47341207-C-T is Pathogenic according to our data. Variant chr11-47341207-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42575.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.1828G>A	p.Asp610Asn	missense	Exon 19 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.1828G>A	p.Asp610Asn	missense	Exon 19 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.1828G>A	p.Asp610Asn	missense	Exon 18 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.1828G>A		non_coding_transcript_exon	Exon 19 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000135 AC: 3 AN: 222558 AF XY: 0.0000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000124 AC: 18 AN: 1446838 Hom.: 0 Cov.: 35 AF XY: 0.0000153 AC XY: 11 AN XY: 718236

African (AFR) AF: 0.0000301 AC: 1 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 42588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83324

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105108

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000128 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:2

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult-onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 6 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count in p.(Asp610His): 14 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Asp610His) has been reported as likely pathogenic but more frequently as a VUS, including in individuals with HCM (ClinVar, cardiodb). In addition, p.(Asp610Glu), p.(Asp610Val) and p.(Asp610Tyr) have been reported as VUS by multiple clinical testing laboratories (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported frequently as a VUS, and in more than 10 individuals with HCM (ClinVar, cardiodb, PMIDs: 32841044, 22857948). It has also been reported as homozygous or compound heterozygous in individuals with childhood onset HCM (PMID: 30009132, ClinVar). In addition, it has been reported as likely pathogenic by a clinical testing laboratory (ClinVar). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 19, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 moderated, PP3 supporting

May 28, 2025

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp610Asn variant in MYBPC3 has been reported in 1 family (index case and affected brother) with autosomal dominant hypertrophic cardiomyopathy. The Asp610Asn variant meets our criteria to be classified as likely pathogenic.

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:2

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 610 of the MYBPC3 protein (p.Asp610Asn). 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. However, some individuals carried additional alleles in cardiomyopathy-related genes. (PMID: 20624503, 22857948, 27532257, 28214152, 28323875, 33782553; internal data). ClinVar contains an entry for this variant (Variation ID: 42575). 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: 34097875). This variant disrupts the p.Asp610 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20624503, 22361390, 25740977). 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.

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a missense variant in the MYBPC3 gene (p.(Asp610Asn)). Missense variants are significantly enriched in patients with HCM and are a known mechanism of disease (PP2) (PMID: 27532257). This variant is present in population databases (GnomAD 3/222558). This variant has been reported in the literature in several unrelated individuals with HCM (PMID:22857948; PMID:20624503; PMID:28214152; PMID:28323875). The variant affects a highly conserved nucleotide and a highly conserved amino acid. Prediction programs classify the variant as pathogenic (Align GVGD:C15; SIFT:pathogenic; MutationTaster: disease causing) (PP3). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.772G>A, classified as pathogenic, BP5). A second unrelated 14-year female patient with HCM presenting with OHCA and sudden cardiac death carried the variant in a homozygous state. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BP5, PP2,PP3).

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant causes a large reduction in protein stability (PMID: 34097875). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 22857948, 27532257, 28214152, 2832387, 33241513, 33782553, 32841044, 35026164, 35581137, ClinVar SCV001572569.1, SCV000059090.5), including one individual who also carried another pathogenic variant in the MYBPC3 gene (PMID: 35581137). Two of the affected individuals were homozygous and had childhood onset of the disease (ClinVar SCV001572569.1, SCV000059090.5). This variant has been identified in 3/222558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Cardiomyopathy Pathogenic:1 Uncertain:1

Jun 09, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant causes a large reduction in protein stability (PMID: 34097875). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 22857948, 27532257, 28214152, 2832387, 33241513, 33782553, 32841044, 35026164, 35581137, ClinVar SCV001572569.1, SCV000059090.5), including one individual who also carried another pathogenic variant in the MYBPC3 gene (PMID: 35581137). Two of the affected individuals were homozygous and had childhood onset of the disease (ClinVar SCV001572569.1, SCV000059090.5). This variant has been identified in 3/222558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

not provided Uncertain:2

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Primary dilated cardiomyopathy Pathogenic:1

Feb 03, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1

Sep 10, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp610Asn variant has not been reported in the literature, however it has be en identified by our laboratory in two individuals with clinical diagnoses of HC M, including one individual of Asian ethnicity who was homozygous for the Asp610 Asn variant and had childhood onset of disease. Aspartic acid (Asp) at position 610 is conserved across mammalian species, however it is not conserved in lower species. In summary, given the available data, the clinical significance of th is variant cannot be determined at this time.

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Cardiovascular phenotype Uncertain:1

Jun 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1828G>A (p.D610N) alteration is located in exon 19 (coding exon 19) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1828, causing the aspartic acid (D) at amino acid position 610 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Uncertain	0.30
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.76
Sift	Benign	0.073	T
Sift4G	Pathogenic	0.0	D
Vest4		0.94
MVP		0.94
MPC		0.81
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.97
Mutation Taster		=51/49	polymorphism

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: rs371564200; hg19: chr11-47362758;