chr11-47334007-C-T

Position:

chr11-47334007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):c.2909G>A(p.Arg970Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000857 in 1,575,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R970W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 1.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2909G>A	p.Arg970Gln	missense_variant	28/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2909G>A	p.Arg970Gln	missense_variant	28/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2909G>A	p.Arg970Gln	missense_variant	27/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000541

AC:

AN:

184920

Hom.:

AF XY:

0.0000603

AC XY:

AN XY:

99582

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000181

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:

0.0000641

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000907

AC:

129

AN:

1422926

Hom.:

Cov.:

AF XY:

0.0000752

AC XY:

AN XY:

704410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000612

Gnomad4 AMR exome

AF:

0.000128

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000296

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Arg970Gln variant in MYBPC3 has been identified in 1 individual with DCM, 2 individuals with HCM, and 1 individual with LVNC (Walsh 2017, Ko 2018, Takasaki 2018, LMM data). It has also been identified in 0.02% (6/28490) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177832). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2023	Identified in several individuals with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Lakdawala et al., 2012; Pugh et al., 2014; Walsh et al., 2017; Ko et al., 2018; Takasaki et al., 2018; van Lint et al., 2019; Hirono et al., 2020; Stava et al., 2022); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24503780, 22464770, 28640247, 30188508, 32600061, 33782553, 35653365, 30847666, 30297972, 27532257, 34819141) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 02, 2018	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces arginine with glutamine at codon 970 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in an individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with glutamine at codon 970 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in an individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 970 of the MYBPC3 protein (p.Arg970Gln). This variant is present in population databases (rs727504346, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 22464770, 27532257, 28640247, 30188508, 30297972). ClinVar contains an entry for this variant (Variation ID: 177832). 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. 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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 16, 2020

Variant summary: MYBPC3 c.2909G>A (p.Arg970Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 184920 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (5.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2909G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Lakdawala_2012, Pugh_2014, Walsh_2017, Ko_2018, Ho_2018, Takasaki_2018). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Left ventricular noncompaction

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

This sequence change in MYBPC3 is predicted to replace arginine with glutamine at codon 970, p.(Arg970Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is not located in an annotated domain. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (114/1,160,438 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction (PMID: 22464770, 27532257, 30847666, 32600061, 32841044). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change, and predicts a benign effect for the missense substitution (REVEL = 0.151). RNA studies have not been conducted to confirm the splicing prediction. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The p.R970Q variant (also known as c.2909G>A), located in coding exon 28 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2909. The arginine at codon 970 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC), but clinical details were limited (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Ko C et al. Genet Med, 2018 01;20:69-75). This variant was also detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.20

CardioboostCm

Benign

0.017

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;T

Eigen

Benign

-0.080

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;.;N

REVEL

Benign

0.15

Sift

Benign

0.63

T;.;T

Sift4G

Benign

0.37

T;T;T

Vest4

0.78

MVP

0.82

MPC

0.81

ClinPred

0.31

GERP RS

5.1

Varity_R

0.19

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.54

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over