11-47333682-C-T

Position:

• chr11-47333682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_000256.3(MYBPC3):​c.3065G>A​(p.Arg1022His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,458,878 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1022P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47333682-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3065G>A	p.Arg1022His	missense_variant	29/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3065G>A	p.Arg1022His	missense_variant	29/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3065G>A	p.Arg1022His	missense_variant	28/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246674 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134018

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1458878 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2024	Identified in patients with HCM in published literature (PMID: 27532257, 28408708, 28790153, 32841044, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28408708, 33782553, 28790153, 27532257, 32841044, 37652022, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 23, 2020	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces arginine with histidine at codon 1022 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28408708, 28790153, 32841044, 33782553). This variant has been identified in 2/278058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg1022Pro and p.Arg1022Cys, have been reported as disease-causing (ClinVar variation ID: 42682 and 42680), suggesting that arginine at this position is important for MYBPC3 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2023	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. ClinVar contains an entry for this variant (Variation ID: 42681). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 33782553; Invitae). 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 sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1022 of the MYBPC3 protein (p.Arg1022His). This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16335287, 20433692, 23396983, 24093860). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 29, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1022His variant in MYBPC3 has been identified in 2 individuals with HCM, one of whom was homozygous (Burns 2017, LMM data). It was also identified in 2/278058 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID#42681). Computational tools suggest that this variant may impact protein function; however, this information is not predictive enough to determine pathogenicity. In addition, two other variants involving this codon, p.Arg1022Cys and p.Arg1022Pro, have been identified in individuals with HCM, suggesting that changes at this position may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM5_Supporting, PP3. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 30, 2023

This missense variant replaces arginine with histidine at codon 1022 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28408708, 28790153, 32841044, 33782553). This variant has been identified in 2/278058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Arg1022Pro and p.Arg1022Cys, have been reported as disease-causing (ClinVar variation ID: 42682 and 42680), suggesting that arginine at this position is important for MYBPC3 protein function. 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. -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 11, 2015

The MYBPC3 Arg1022His is a rare variant and is present in the 1000 genomes project (MAF=0.0002; http://www.1000genomes.org/), and absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in 1 HCM proband of Indian descent, who was heterozygous for MYBPC3 Arg1022His, and also carries another variant (LDB3 Gln97Arg) of "uncertain significance". The proband has no family history of disease or SCD. Interestingly, different rare variants at this position (Arg1022Cys, Arg1022Pro, Arg1022Ser) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. In summary, based on rarity in the general population and our limited familial data, we have classified MYBPC3 Arg1022His as a variant of "uncertain significance". Further evidence is required to fully understand its pathogenic role in HCM. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Uncertain	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.014	D;D;D
Vest4		0.84
MVP		0.93
MPC		0.92
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.42
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516000; hg19: chr11-47355233;