11-47333640-C-T

Variant names:

• chr11-47333640-C-T
• rs374255381
• NM_000256.3:c.3107G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):​c.3107G>A​(p.Arg1036His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000709 in 1,608,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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. R1036C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.227
• Publications: 2 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093043804).

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.3107G>A	p.Arg1036His	missense	Exon 29 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.3107G>A	p.Arg1036His	missense	Exon 29 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.3107G>A	p.Arg1036His	missense	Exon 28 of 34	ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152240 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000612 AC: 15 AN: 245264 AF XY: 0.0000674

Gnomad AFR exome AF: 0.0000644

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: 0.000106

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000714 AC: 104 AN: 1456138 Hom.: 0 Cov.: 32 AF XY: 0.0000649 AC XY: 47 AN XY: 724692

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 47970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1111800

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:2

Jul 07, 2015

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 03, 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 1036 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 26914223, 28356264). This variant has been identified in 17/276658 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.

not specified Uncertain:1 Benign:1

Jul 06, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R1036H variant has been reported in one patient with HCM (Lopes et al., 2015); however, familial segregation information, in vitro functional studies and additional clinical information was not included. The R1036H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the R1036H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and where H1036 is the wild type in several species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

Jan 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg1036His in exon 29 of MYBPC3: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 10 mammals have a histidine (His) at this position despite high nearby a mino acid conservation. This variant has also been identified in 1 individual wi th HCM (Lopes 2015) and 6/66506 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374255381).

not provided Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypertrophic cardiomyopathy Uncertain:1

Jan 15, 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 1036 of the MYBPC3 protein (p.Arg1036His). This variant is present in population databases (rs374255381, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28356264). ClinVar contains an entry for this variant (Variation ID: 181000). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Cardiovascular phenotype Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1036H variant (also known as c.3107G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3107. The arginine at codon 1036 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited and other cardiac-related alterations were identified in some individuals (Lopes LR et al. Heart, 2015 Feb;101:294-301; Murphy SL et al. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61 Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Benign	0.0018
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.23
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.081
Sift	Benign	0.063	T
Sift4G	Benign	0.080	T
Vest4		0.11
MVP		0.75
MPC		0.27
ClinPred		0.085	T
GERP RS		-0.76
Varity_R		0.068
gMVP		0.31
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs374255381; hg19: chr11-47355191; COSMIC: COSV99920660; COSMIC: COSV99920660;