rs1800565

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_000256.3(MYBPC3):c.1961G>A(p.Arg654His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign 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. R654G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 2.33

Publications

12 publications found

Variant links:

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

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47339758-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 180410.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1972478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1961G>A	p.Arg654His	missense_variant	Exon 21 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.1961G>A	p.Arg654His	missense_variant	Exon 21 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1961G>A	p.Arg654His	missense_variant	Exon 20 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1961G>A		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249152

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111740

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000180

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Aug 24, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 654 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. In vitro functional studies have shown that this variant is likely to affect intramolecular interactions (PMID: 12386147, 12787675). This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 9541115, 11447480, 25132132). This variant has been identified in 6/249152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy

Uncertain:2

Dec 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 histidine, which is basic and polar, at codon 654 of the MYBPC3 protein (p.Arg654His). This variant is present in population databases (rs1800565, gnomAD 0.02%). This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 9541115, 11447480, 37937776). ClinVar contains an entry for this variant (Variation ID: 42588). 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 tolerated. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 12386147). 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. -

Dec 01, 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 arginine with histidine at codon 654 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In vitro functional studies have shown that this variant is likely to affect intramolecular interactions (PMID: 12386147, 12787675). This variant has been reported in an individual affected with hypertrophic cardiomyopathy and in his three asymptomatic offsprings (PMID: 9541115, 11447480). This variant has also been identified in 6/249152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4

Pathogenic:1

May 03, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg654His variant in MYBPC3 has been reported in 1 individual with HCM (Moolman-Smook 1998) and 0.016% (3/17976) East Asian chromosomes by gnomAD. Functional studies suggest that this variant may impact the protein; though, it is not clear whether this would result in disease (Moolman-Smook 1998, Idowu 2003). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None. -

Left ventricular noncompaction 10

Uncertain:1

Jun 24, 2022

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-3C. 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), left ventricular noncompaction 10 (MIM#615396) and dilated cardiomyopathy 1MM (MIM#615396) however, the ClinGen expert panel have assessed gene-disease association with DCM as limited. (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however, recessive inheritance results in a more severe early-onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity in HCM (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 5 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated C5 domain (PMID: 12386147). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Alternative changes to cysteine and glycine at the same amino acid residue have been reported in individuals with HCM or DCM, and also as VUS (ClinVar, PMIDs: 27532257, 21750094, 30984009, 25351510). However, both are more major amino acid changes. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as heterozygous in individuals with HCM (PMIDs: 9541115, 25132132) and also as VUS (ClinVar). (I) 1010 - Functional evidence for this variant is inconclusive. An in vitro study showed the MYBPC3 protein domain C5 in R654H mutant had significantly weaker binding to domain C8-C10 compared with wild type (PMID: 12386147). Another study showed R654H protein had normal folding and stability (PMID: 12787675). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Mar 09, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1961G>A (p.R654H) alteration is located in exon 21 (coding exon 21) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1961, causing the arginine (R) at amino acid position 654 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.0043

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.77

N;.;.

PhyloP100

2.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.61

N;.;N

REVEL

Benign

0.26

Sift

Benign

0.40

T;.;T

Sift4G

Benign

0.14

T;T;T

Vest4

0.70

MVP

0.86

MPC

0.29

ClinPred

0.12

GERP RS

4.9

Varity_R

0.051

gMVP

0.45

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over