rs776734314

Positions:

• chr11-47342878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_000256.3(MYBPC3):​c.1409G>A​(p.Arg470Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,118 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. R470W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 5.78

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 5 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 13 benign (80%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47342879-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1677581.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1409G>A	p.Arg470Gln	missense_variant	16/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1409G>A	p.Arg470Gln	missense_variant	16/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1409G>A	p.Arg470Gln	missense_variant	15/34	5		A2
MYBPC3	ENST00000544791.1	c.1409G>A	p.Arg470Gln	missense_variant, NMD_transcript_variant	16/27	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247146 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460758 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726560

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 470 of the MYBPC3 protein (p.Arg470Gln). This variant is present in population databases (rs776734314, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27483260, 27600940, 29398688; Invitae). ClinVar contains an entry for this variant (Variation ID: 403203). 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. This variant disrupts the p.Arg470 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23233322, 33782553). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2023	This missense variant replaces arginine with glutamine at codon 470 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: 27483260, 27600940, 29398688, 33495597) and in an individual affected with aortic dissection (PMID: 30959811). This variant has been identified in 1/247146 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2024	Variant summary: MYBPC3 c.1409G>A (p.Arg470Gln) results in a conservative amino acid change in Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1409G>A has been reported in the literature in several individuals affected with HCM or undertaking Cardiomyopathy panel testing (Harris_2011, Teramoto_2018, Emrahi_2022). In a large cross-sectional study with individuals referred for diagnostic sequencing for HCM and DCM, this variant was evaluated as a VUS change with penetrance of 0.017 (McGurk_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21415409, 37652022, 29398688, Emrahi et al). ClinVar contains an entry for this variant (Variation ID: 403203). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 1/11104 Latino; -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 23, 2023	This missense variant replaces arginine with glutamine at codon 470 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: 27483260, 27600940, 29398688, 33495597) and in an individual affected with aortic dissection (PMID: 30959811). This variant has been identified in 1/247146 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 11, 2015	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2019

Reported in association with HCM (Rubattu et al., 2016; Cecconi et al., 2016; Teramoto et al., 2018); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 403203; 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: 27483260, 25320358, 28679633, 27600940, 21415409, 29398688) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.R470Q variant (also known as c.1409G>A), located in coding exon 16 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1409. The arginine at codon 470 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts, as well as a sudden unexplained death cohort (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Teramoto R et al. Circ J, 2018 03;82:1139-1148; Hata Y et al. J Clin Med, 2019 Apr;8:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostCm	Uncertain	0.85
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.95
MVP		0.75
MPC		0.88
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.41
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs776734314; hg19: chr11-47364429; COSMIC: COSV57028051;